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Burns AJ, Goldstein AM. Causes and consequences: development and pathophysiology of Hirschsprung disease. WORLD JOURNAL OF PEDIATRIC SURGERY 2024; 7:e000903. [PMID: 39600627 PMCID: PMC11590806 DOI: 10.1136/wjps-2024-000903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 10/29/2024] [Indexed: 11/29/2024] Open
Abstract
Hirschsprung disease (HSCR) is a congenital enteric neuropathy in which the enteric nervous system (ENS) fails to develop along variable lengths of the distal gastrointestinal (GI) tract. This aganglionosis results in a functional bowel obstruction and requires surgical resection of the aganglionic segment. Despite surgery, however, long-term bowel dysfunction affects many patients. Understanding the embryologic causes and pathophysiologic consequences of HSCR is critical to improving its diagnosis and treatment. During normal gut development, the ENS arises from neural crest cells (NCCs) that delaminate from the neural tube to populate the entire GI tract with enteric neurons and glia. This process requires NCCs to undergo proliferation, migration and differentiation to form the complex neuroglial network that regulates gut motility and other intestinal functions. This review discusses the cellular and molecular processes that control normal ENS formation and what goes awry to give rise to HSCR. The complex pathophysiologic consequences of aganglionosis are discussed, including recent observations that describe novel aspects of HSCR beyond the absence of ganglion cells. This review aims to expand the understanding of HSCR and to stimulate new ideas on how to improve current management of the disease.
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Affiliation(s)
- Alan J Burns
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Kuil LE, Chauhan RK, de Graaf BM, Cheng WW, Kakiailatu NJM, Lasabuda R, Verhaeghe C, Windster JD, Schriemer D, Azmani Z, Brooks AS, Edie S, Reeves RH, Eggen BJL, Shepherd IT, Burns AJ, Hofstra RMW, Melotte V, Brosens E, Alves MM. ATP5PO levels regulate enteric nervous system development in zebrafish, linking Hirschsprung disease to Down Syndrome. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166991. [PMID: 38128843 DOI: 10.1016/j.bbadis.2023.166991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 12/09/2023] [Accepted: 12/11/2023] [Indexed: 12/23/2023]
Abstract
Hirschsprung disease (HSCR) is a complex genetic disorder characterized by the absence of enteric nervous system (ENS) in the distal region of the intestine. Down Syndrome (DS) patients have a >50-fold higher risk of developing HSCR than the general population, suggesting that overexpression of human chromosome 21 (Hsa21) genes contribute to HSCR etiology. However, identification of responsible genes remains challenging. Here, we describe a genetic screening of potential candidate genes located on Hsa21, using the zebrafish. Candidate genes were located in the DS-HSCR susceptibility region, expressed in the human intestine, were known potential biomarkers for DS prenatal diagnosis, and were present in the zebrafish genome. With this approach, four genes were selected: RCAN1, ITSN1, ATP5PO and SUMO3. However, only overexpression of ATP5PO, coding for a component of the mitochondrial ATPase, led to significant reduction of ENS cells. Paradoxically, in vitro studies showed that overexpression of ATP5PO led to a reduction of ATP5PO protein levels. Impaired neuronal differentiation and reduced mitochondrial ATP production, were also detected in vitro, after overexpression of ATP5PO in a neuroblastoma cell line. Finally, epistasis was observed between ATP5PO and ret, the most important HSCR gene. Taken together, our results identify ATP5PO as the gene responsible for the increased risk of HSCR in DS patients in particular if RET variants are also present, and show that a balanced expression of ATP5PO is required for normal ENS development.
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Affiliation(s)
- L E Kuil
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - R K Chauhan
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - B M de Graaf
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - W W Cheng
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - N J M Kakiailatu
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - R Lasabuda
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - C Verhaeghe
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - J D Windster
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Pediatric Surgery, Erasmus University Medical Center Rotterdam, Sophia's Children's Hospital, Rotterdam, the Netherlands
| | - D Schriemer
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Z Azmani
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - A S Brooks
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - S Edie
- Johns Hopkins University School of Medicine, Department of Physiology and McKusick-Nathans Department of Genetic Medicine, Baltimore, MD, United States of America
| | - R H Reeves
- Johns Hopkins University School of Medicine, Department of Physiology and McKusick-Nathans Department of Genetic Medicine, Baltimore, MD, United States of America
| | - B J L Eggen
- Department of Biomedical Sciences of Cells and Systems, Section Molecular Neurobiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - I T Shepherd
- Department of Biology, Emory University, Atlanta, GA, United States of America
| | - A J Burns
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands; Birth Defects Research Centre, UCL Institute of Child Health, London, United Kingdom; Gastrointestinal Drug Discovery Unit, Takeda Pharmaceuticals, Cambridge, MA, United States of America
| | - R M W Hofstra
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - V Melotte
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Pathology, GROW-school for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands
| | - E Brosens
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands
| | - M M Alves
- Department of Clinical Genetics, Erasmus University Medical Center Rotterdam - Sophia Children's Hospital, Rotterdam, the Netherlands; Department of Pediatric Surgery, Erasmus University Medical Center Rotterdam, Sophia's Children's Hospital, Rotterdam, the Netherlands.
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Ding HY, Lei W, Xiao SJ, Deng H, Yuan LK, Xu L, Zhou JL, Huang R, Fang YL, Wang QY, Zhang Y, Zhang L, Zhu XC. High incidence of EDNRB gene mutation in seven southern Chinese familial cases with Hirschsprung's disease. Pediatr Surg Int 2024; 40:38. [PMID: 38253735 DOI: 10.1007/s00383-023-05620-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/15/2023] [Indexed: 01/24/2024]
Abstract
PURPOSE Hirschsprung's disease (HSCR) is the leading cause of neonatal functional intestinal obstruction, which has been identified in many familial cases. HSCR, a multifactorial disorder of enteric nervous system (ENS) development, is associated with at least 24 genes and seven chromosomal loci, with RET and EDNRB as its major genes. We present a genetic investigation of familial HSCR to clarify the genotype-phenotype relationship. METHODS We performed whole exome sequencing (WES) on Illumina HiSeq X Ten platform to investigate genetic backgrounds of core family members, and identified the possibly harmful mutation genes. Mutation carriers and pedigree relatives were validated by Sanger sequencing for evaluating the gene penetrance. RESULTS Four familial cases showed potential disease-relative variants in EDNRB and RET gene, accounting for all detection rate of 57.1%. Three familial cases exhibited strong pathogenic variants as frameshift or missense mutations in EDNRB gene. A novel c.367delinsTT mutation of EDNRB was identified in one family member. The other two EDNRB mutations, c.553G>A in family 2 and c.877delinsTT in family 5, have been reported in previous literatures. The penetrance of EDNRB variants was 33-50% according mutation carries. In family 6, the RET c.1858T>C (C620R) point mutation has previously been reported to cause HSCR, with 28.5% penetrance. CONCLUSION We identified a novel EDNRB (deleted C and inserted TT) mutation in this study using WES. Heterozygote variations in EDNRB gene were significantly enriched in three families and RET mutations were identified in one family. EDNRB variants showed an overall higher incidence and penetrance than RET in southern Chinese families cases.
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Affiliation(s)
- Hui-Yang Ding
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Wen Lei
- Maternal and Child Health Research Institute, Translational Medicine Center, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Shang-Jie Xiao
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Hua Deng
- Maternal and Child Health Research Institute, Translational Medicine Center, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Li-Ke Yuan
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Lu Xu
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Jia-Liang Zhou
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Rong Huang
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Yuan-Long Fang
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Qing-Yuan Wang
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Ying Zhang
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China
| | - Liang Zhang
- Maternal and Child Health Research Institute, Translational Medicine Center, Guangdong Women and Children Hospital, Guangzhou, 511400, China.
| | - Xiao-Chun Zhu
- Department of Neonatal Surgery, Guangdong Women and Children Hospital, Guangzhou, 511400, China.
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Pelizzo MR, Mazza EI, Mian C, Merante Boschin I. Medullary thyroid carcinoma. Expert Rev Anticancer Ther 2023; 23:943-957. [PMID: 37646181 DOI: 10.1080/14737140.2023.2247566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 08/09/2023] [Indexed: 09/01/2023]
Abstract
INTRODUCTION Medullary thyroid carcinoma (MTC) constitutes approximately 5-10% of all thyroid cancers. Although the tumor forms in the thyroid, it doesn't originate from thyroid cells, but from the C cells or parafollicular cells which produce and release a hormone called calcitonin (CT). Starting from the second half of the 1900s, MTC was progressively studied and defined. AREAS COVERED This study aims to analyze the history, clinical presentation and biological behavior of MTC, bio-humoral and instrumental diagnosis, molecular profiling, genetic screening, preoperative staging and instrumental procedures, indispensable in expert and dedicated hands, such as high-resolution ultrasonography, CT-scan, MRI and PET/TC. We examine recommended and controversial surgical indications and procedures, prophylactic early surgery and multiple endocrine neoplasia surgery. Also, we discuss pathological anatomy classification and targeted therapies. The role of serum CT is valued both as undisputed and constant preoperative diagnostic marker, obscuring cytology and as early postoperative marker that predicts disease persistence. EXPERT OPINION With a complete preoperative study, unnecessary or useless, late and extended interventions can be reduced in favor of tailored surgery that also considers quality of life. Finally, great progress has been made in targeted therapy, with favorable impact on survival.
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Affiliation(s)
- Maria Rosa Pelizzo
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Esmeralda Isabella Mazza
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Caterina Mian
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
| | - Isabella Merante Boschin
- Department of Surgical, Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy
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Xiao J, Hao LW, Wang J, Yu XS, You JY, Li ZJ, Mao HD, Meng XY, Feng JX. Comprehensive characterization of the genetic landscape of familial Hirschsprung's disease. World J Pediatr 2023; 19:644-651. [PMID: 36857021 PMCID: PMC10258170 DOI: 10.1007/s12519-023-00686-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 01/09/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Hirschsprung's disease (HSCR) is one of the most common congenital digestive tract malformations and can cause stubborn constipation or gastrointestinal obstruction after birth, causing great physical and mental pain to patients and their families. Studies have shown that more than 20 genes are involved in HSCR, and most cases of HSCR are sporadic. However, the overall rate of familial recurrence in 4331 cases of HSCR is about 7.6%. Furthermore, familial HSCR patients show incomplete dominance. We still do not know the penetrance and genetic characteristics of these known risk genes due to the rarity of HSCR families. METHODS To find published references, we used the title/abstract terms "Hirschsprung" and "familial" in the PubMed database and the MeSH terms "Hirschsprung" and "familial" in Web of Science. Finally, we summarized 129 HSCR families over the last 40 years. RESULTS The male-to-female ratio and the percentage of short segment-HSCR in familial HSCR are much lower than in sporadic HSCR. The primary gene factors in the syndromic families are ret proto-oncogene (RET) and endothelin B receptor gene (EDNRB). Most families show incomplete dominance and are relevant to RET, and the RET mutation has 56% penetrance in familial HSCR. When one of the parents is a RET mutation carrier in an HSCR family, the offspring's recurrence risk is 28%, and the incidence of the offspring does not depend on whether the parent suffers from HSCR. CONCLUSION Our findings will help HSCR patients obtain better genetic counseling, calculate the risk of recurrence, and provide new insights for future pedigree studies.
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Affiliation(s)
- Jun Xiao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China
| | - Lu-Wen Hao
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
| | - Jing Wang
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China
| | - Xiao-Si Yu
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China
| | - Jing-Yi You
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China
| | - Ze-Jian Li
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China
| | - Han-Dan Mao
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China
| | - Xin-Yao Meng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China.
| | - Jie-Xiong Feng
- Department of Pediatric Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, 430030, China.
- Hubei Clinical Center of Hirschsprung's Disease and Allied Disorders, Wuhan, 430030, China.
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Dental pulp stem cells as a therapy for congenital entero-neuropathy. Sci Rep 2022; 12:6990. [PMID: 35484137 PMCID: PMC9051124 DOI: 10.1038/s41598-022-10077-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 03/22/2022] [Indexed: 11/09/2022] Open
Abstract
Hirschsprung's disease is a congenital entero-neuropathy that causes chronic constipation and intestinal obstruction. New treatments for entero-neuropathy are needed because current surgical strategies have limitations5. Entero-neuropathy results from enteric nervous system dysfunction due to incomplete colonization of the distal intestine by neural crest-derived cells. Impaired cooperation between the enteric nervous system and intestinal pacemaker cells may also contribute to entero-neuropathy. Stem cell therapy to repair these multiple defects represents a novel treatment approach. Dental pulp stem cells derived from deciduous teeth (dDPSCs) are multipotent cranial neural crest-derived cells, but it remains unknown whether dDPSCs have potential as a new therapy for entero-neuropathy. Here we show that intravenous transplantation of dDPSCs into the Japanese Fancy-1 mouse, an established model of hypoganglionosis and entero-neuropathy, improves large intestinal structure and function and prolongs survival. Intravenously injected dDPSCs migrate to affected regions of the intestine through interactions between stromal cell-derived factor-1α and C-X-C chemokine receptor type-4. Transplanted dDPSCs differentiate into both pacemaker cells and enteric neurons in the proximal colon to improve electrical and peristaltic activity, in addition to their paracrine effects. Our findings indicate that transplanted dDPSCs can differentiate into different cell types to correct entero-neuropathy-associated defects.
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Mu J, Zhang Y, Liao G, Li X, Luo Y, Huang Z, Luo C, Wu K. Association of rs2435357 and rs2506030 polymorphisms in RET with susceptibility to hirschsprung disease: A systematic review and meta-analysis. Front Pediatr 2022; 10:1030933. [PMID: 36324815 PMCID: PMC9618721 DOI: 10.3389/fped.2022.1030933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND There are numerous published studies on the association between RET polymorphisms and susceptibility to Hirschsprung disease (HSCR). However, some of the results are inconsistent and the studies were conducted with small sample sizes. Therefore, we performed a meta-analysis to clarify the relationship. METHODS Relevant data were retrieved from PubMed, Web of Science, Cochrane Library, EMBASE, CNKI, and Google Scholar according to PRISMA guidelines. Odds ratios (OR) were calculated to assess susceptibility to HSCR. Meanwhile, heterogeneity and publication bias were also calculated by R software package (version 4.2.1). The protocol was published in PROSPERO (CRD42022348940). RESULTS A total of 12 studies were included in the meta-analysis and comprised 12 studies on the RET polymorphism rs2435357 (1,939 subjects and 3,613 controls) and 7 studies on the RET polymorphism rs2506030 (1,849 patients with HSCR and 3,054 controls). The analysis revealed that rs2435357 [A vs. G: odds ratio (OR) = 3.842, 95% confidence interval (CI) 2.829-5.220; AA vs. GG: OR = 2.597, 95% CI 1.499-4.501; AA + AG vs. GG: OR = 6.789, 95% CI 3.0711-14.9973; AA vs. AG + GG: OR = 8.156, 95%CI 5.429-12.253] and rs2506030 (A vs. G: OR = 0.519, 95% CI 0.469-0.573; AA vs. GG: OR = 0.543, 95% CI 0.474-0.623; AA + AG vs. GG: OR = 0.410, 95% CI 0.360-0.468; AA vs. AG + GG: OR = 0.361, 95%CI 0.292-0.447) were significantly associated with susceptibility to HSCR. CONCLUSIONS The polymorphisms rs2435357 and rs2506030 in the RET may be related to susceptibility to HSCR, of which rs2435357 (T > C) is the causal locus and rs2506030 (A > G) is the protective locus. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/, identifier:CRD42022348940.
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Affiliation(s)
- Jianhua Mu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yuxi Zhang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Guoying Liao
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Xinxin Li
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Yinyan Luo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhaorong Huang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Caiyun Luo
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, Guangdong, China
| | - Kai Wu
- Department of Pediatric Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease. Int J Mol Sci 2021; 22:ijms222313140. [PMID: 34884944 PMCID: PMC8658428 DOI: 10.3390/ijms222313140] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Revised: 11/30/2021] [Accepted: 12/03/2021] [Indexed: 12/13/2022] Open
Abstract
Hirschsprung disease is a congenital malformation where ganglia of the neural crest-derived enteric nervous system are missing over varying lengths of the distal gastrointestinal tract. This complex genetic condition involves both rare and common variants in dozens of genes, many of which have been functionally validated in animal models. Modifier loci present in the genetic background are also believed to influence disease penetrance and severity, but this has not been frequently tested in animal models. Here, we addressed this question using Holstein mice in which aganglionosis is due to excessive deposition of collagen VI around the developing enteric nervous system, thereby allowing us to model trisomy 21-associated Hirschsprung disease. We also asked whether the genetic background might influence the response of Holstein mice to GDNF enemas, which we recently showed to have regenerative properties for the missing enteric nervous system. Compared to Holstein mice in their original FVB/N genetic background, Holstein mice maintained in a C57BL/6N background were found to have a less severe enteric nervous system defect and to be more responsive to GDNF enemas. This change of genetic background had a positive impact on the enteric nervous system only, leaving the neural crest-related pigmentation phenotype of Holstein mice unaffected. Taken together with other similar studies, these results are thus consistent with the notion that the enteric nervous system is more sensitive to genetic background changes than other neural crest derivatives.
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Karim A, Tang CSM, Tam PKH. The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications. Front Pediatr 2021; 9:638093. [PMID: 34422713 PMCID: PMC8374333 DOI: 10.3389/fped.2021.638093] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2020] [Accepted: 07/02/2021] [Indexed: 12/25/2022] Open
Abstract
Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500-5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.
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Affiliation(s)
- Anwarul Karim
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Clara Sze-Man Tang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Li Dak-Sum Research Center, The University of Hong Kong—Karolinska Institute Collaboration in Regenerative Medicine, Hong Kong, China
| | - Paul Kwong-Hang Tam
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
- Li Dak-Sum Research Center, The University of Hong Kong—Karolinska Institute Collaboration in Regenerative Medicine, Hong Kong, China
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Adams SE, Purkiss AG, Knowles PP, Nans A, Briggs DC, Borg A, Earl CP, Goodman KM, Nawrotek A, Borg AJ, McIntosh PB, Houghton FM, Kjær S, McDonald NQ. A two-site flexible clamp mechanism for RET-GDNF-GFRα1 assembly reveals both conformational adaptation and strict geometric spacing. Structure 2021; 29:694-708.e7. [PMID: 33484636 PMCID: PMC8266384 DOI: 10.1016/j.str.2020.12.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 12/07/2020] [Accepted: 12/18/2020] [Indexed: 11/04/2022]
Abstract
RET receptor tyrosine kinase plays vital developmental and neuroprotective roles in metazoans. GDNF family ligands (GFLs) when bound to cognate GFRα co-receptors recognize and activate RET stimulating its cytoplasmic kinase function. The principles for RET ligand-co-receptor recognition are incompletely understood. Here, we report a crystal structure of the cadherin-like module (CLD1-4) from zebrafish RET revealing interdomain flexibility between CLD2 and CLD3. Comparison with a cryo-electron microscopy structure of a ligand-engaged zebrafish RETECD-GDNF-GFRα1a complex indicates conformational changes within a clade-specific CLD3 loop adjacent to the co-receptor. Our observations indicate that RET is a molecular clamp with a flexible calcium-dependent arm that adapts to different GFRα co-receptors, while its rigid arm recognizes a GFL dimer to align both membrane-proximal cysteine-rich domains. We also visualize linear arrays of RETECD-GDNF-GFRα1a suggesting that a conserved contact stabilizes higher-order species. Our study reveals that ligand-co-receptor recognition by RET involves both receptor plasticity and strict spacing of receptor dimers by GFL ligands.
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Affiliation(s)
- Sarah E Adams
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Andrew G Purkiss
- Structural Biology Science Technology Platform, Francis Crick Institute, NW1 1AT London, UK
| | - Phillip P Knowles
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Andrea Nans
- Structural Biology Science Technology Platform, Francis Crick Institute, NW1 1AT London, UK
| | - David C Briggs
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Annabel Borg
- Structural Biology Science Technology Platform, Francis Crick Institute, NW1 1AT London, UK
| | - Christopher P Earl
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Kerry M Goodman
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Agata Nawrotek
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Aaron J Borg
- Mass Spectrometry Science Technology Platform, Francis Crick Institute, NW1 1AT London, UK
| | - Pauline B McIntosh
- Structural Biology of Cells and Viruses Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK
| | - Francesca M Houghton
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK
| | - Svend Kjær
- Structural Biology Science Technology Platform, Francis Crick Institute, NW1 1AT London, UK
| | - Neil Q McDonald
- Signalling and Structural Biology Laboratory, Francis Crick Institute, NW1 1AT London, UK; Institute of Structural and Molecular Biology, Department of Biological Sciences, Birkbeck College, Malet Street, London WC1E 7HX, UK.
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11
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Diposarosa R, Bustam N, Sahiratmadja E, Susanto P, Sribudiani Y. Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung's disease. Heliyon 2021; 7:e07308. [PMID: 34195419 PMCID: PMC8237298 DOI: 10.1016/j.heliyon.2021.e07308] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 03/16/2021] [Accepted: 06/10/2021] [Indexed: 01/13/2023] Open
Abstract
Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system (ENS) derived from neural crest cells (NCCs), which affects their migration, proliferation, differentiation, or preservation in the digestive tract, resulting in aganglionosis in the distal intestine. The regulation of both NCCs and the surrounding environment involves various genes, signaling pathways, transcription factors, and morphogens. Therefore, changes in gene expression during the development of the ENS may contribute to the pathogenesis of HSCR. This review discusses several mechanisms involved in the development of ENS, confirming that deviant genetic and epigenetic patterns, such as DNA methylation, histone modification, and microRNA (miRNA) regulation, can contribute to the development of neurocristopathy. Specifically, the epigenetic regulation of miRNA expression and its relationship to cellular interactions and gene activation through various major pathways in Hirschsprung's disease will be discussed.
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Affiliation(s)
- R. Diposarosa
- Department of Surgery, Division of Pediatric Surgery, Dr. Hasan Sadikin General Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - N.A. Bustam
- Department of Surgery, Division of Pediatric Surgery, Dr. Hasan Sadikin General Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Edhyana Sahiratmadja
- Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
- Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - P.S. Susanto
- Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Y. Sribudiani
- Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
- Research Center of Medical Genetics, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
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12
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Le TL, Galmiche L, Levy J, Suwannarat P, Hellebrekers DM, Morarach K, Boismoreau F, Theunissen TE, Lefebvre M, Pelet A, Martinovic J, Gelot A, Guimiot F, Calleroz A, Gitiaux C, Hully M, Goulet O, Chardot C, Drunat S, Capri Y, Bole-Feysot C, Nitschké P, Whalen S, Mouthon L, Babcock HE, Hofstra R, de Coo IF, Tabet AC, Molina TJ, Keren B, Brooks A, Smeets HJ, Marklund U, Gordon CT, Lyonnet S, Amiel J, Bondurand N. Dysregulation of the NRG1/ERBB pathway causes a developmental disorder with gastrointestinal dysmotility in humans. J Clin Invest 2021; 131:145837. [PMID: 33497358 DOI: 10.1172/jci145837] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
Hirschsprung disease (HSCR) is the most frequent developmental anomaly of the enteric nervous system, with an incidence of 1 in 5000 live births. Chronic intestinal pseudo-obstruction (CIPO) is less frequent and classified as neurogenic or myogenic. Isolated HSCR has an oligogenic inheritance with RET as the major disease-causing gene, while CIPO is genetically heterogeneous, caused by mutations in smooth muscle-specific genes. Here, we describe a series of patients with developmental disorders including gastrointestinal dysmotility, and investigate the underlying molecular bases. Trio-exome sequencing led to the identification of biallelic variants in ERBB3 and ERBB2 in 8 individuals variably associating HSCR, CIPO, peripheral neuropathy, and arthrogryposis. Thorough gut histology revealed aganglionosis, hypoganglionosis, and intestinal smooth muscle abnormalities. The cell type-specific ErbB3 and ErbB2 function was further analyzed in mouse single-cell RNA sequencing data and in a conditional ErbB3-deficient mouse model, revealing a primary role for ERBB3 in enteric progenitors. The consequences of the identified variants were evaluated using quantitative real-time PCR (RT-qPCR) on patient-derived fibroblasts or immunoblot assays on Neuro-2a cells overexpressing WT or mutant proteins, revealing either decreased expression or altered phosphorylation of the mutant receptors. Our results demonstrate that dysregulation of ERBB3 or ERBB2 leads to a broad spectrum of developmental anomalies, including intestinal dysmotility.
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Affiliation(s)
- Thuy-Linh Le
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
| | - Louise Galmiche
- INSERM UMR 1235, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, University of Nantes, Nantes, France.,Pathology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France
| | - Jonathan Levy
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.,Université de Paris, NeuroDiderot, INSERM UMR 1141, Paris, France
| | - Pim Suwannarat
- Department of Genetics, Mid-Atlantic Permanente Medical Group, Suitland, Maryland, USA
| | - Debby Mei Hellebrekers
- Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, Netherlands
| | - Khomgrit Morarach
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Franck Boismoreau
- Institut de Biologie de l'ENS (IBENS), INSERM, CNRS, École Normale Supérieure, PSL Research University, Paris, France
| | - Tom Ej Theunissen
- Department of Genetics and Cell Biology, Maastricht University, Maastricht, Netherlands
| | - Mathilde Lefebvre
- Fetal Pathology Unit, Armand Trousseau Hospital, AP-HP, Paris, France
| | - Anna Pelet
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
| | - Jelena Martinovic
- Fetal Pathology Unit, Antoine Béclère Hospital, AP-HP, Paris-Saclay University, Clamart, France
| | - Antoinette Gelot
- Neuropathology, Pathology Department, Armand Trousseau Hospital, AP-HP, Paris, France.,Aix-Marseille University, INMED INSERM UMR1249, Campus de Luminy, Marseille, France
| | - Fabien Guimiot
- Université de Paris, NeuroDiderot, INSERM UMR 1141, Paris, France.,Fetal Pathology Unit, Robert Debré Hospital, AP-HP, Paris, France
| | - Amanda Calleroz
- Pathology and Laboratory Medicine Division, Children's National Hospital, Washington DC, USA
| | - Cyril Gitiaux
- Department of Pediatric Clinical Neurophysiology, Necker-Enfants Malades Hospital, AP-HP, Université de Paris, Paris, France
| | - Marie Hully
- Department of Pediatric Neurology and Rehabilitation, Necker-Enfants Malades Hospital, AP-HP, Université de Paris, Paris, France
| | - Olivier Goulet
- Department of Pediatric Gastroenterology-Hepatology-Nutrition, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Christophe Chardot
- Department of Pediatric Surgery, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Severine Drunat
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.,Université de Paris, NeuroDiderot, INSERM UMR 1141, Paris, France
| | - Yline Capri
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France
| | - Christine Bole-Feysot
- Genomics Core Facility, Imagine Institute-Structure Federative de Recherche Necker, INSERM UMR 1163 and INSERM US24/CNRS UMS 3633, Université de Paris, Paris, France
| | | | - Sandra Whalen
- Clinical Genetics Unit and Reference Center, Anomalies du Développement et Syndromes Malformatifs, AP-HP, Sorbonne University, Armand Trousseau Hospital, Paris, France
| | - Linda Mouthon
- Department of Genetics, La Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Holly E Babcock
- Children's National Hospital, Rare Disease Institute, Washington, DC, USA
| | - Robert Hofstra
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Irenaeus Fm de Coo
- Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, Netherlands
| | - Anne-Claude Tabet
- Genetics Department, Robert Debré Hospital, AP-HP, Paris, France.,Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France
| | - Thierry J Molina
- Pathology Department, Assistance Publique Hôpitaux de Paris (AP-HP), Necker-Enfants Malades Hospital, Paris, France.,Université de Paris, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France
| | - Boris Keren
- Department of Genetics, La Pitié-Salpêtrière Hospital, AP-HP, Paris, France
| | - Alice Brooks
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, Netherlands
| | - Hubert Jm Smeets
- Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, Netherlands
| | - Ulrika Marklund
- Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - Christopher T Gordon
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
| | - Stanislas Lyonnet
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France.,Fédération de Génétique, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Jeanne Amiel
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France.,Fédération de Génétique, Necker-Enfants Malades Hospital, AP-HP, Paris, France
| | - Nadège Bondurand
- Laboratory of Embryology and Genetics of Human Malformation, Imagine Institute, INSERM UMR 1163, Université de Paris, Paris, France
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13
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Wang G, Wang H, Zhang L, Guo F, Wu X, Liu Y. MiR-195-5p inhibits proliferation and invasion of nerve cells in Hirschsprung disease by targeting GFRA4. Mol Cell Biochem 2021; 476:2061-2073. [PMID: 33515383 DOI: 10.1007/s11010-021-04055-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 01/11/2021] [Indexed: 12/18/2022]
Abstract
Studies have reported that miR-195-5p plays a role in the Hirschsprung disease (HSCR). Our previous work found GDNF family receptor alpha 4 (GFRA4) is also associated with HSCR. In this study, we focused on whether miR-195-5p induces the absence of enteric neurons and enteric neural crest in HSCR by regulating GFRA4. The expression levels of GFRA4 and miR-195-5p in colon tissues were evaluated by real-time PCR (RT-PCR) assay. We overexpressed GFRA4 or miR-195-5p in SH-SY5Y cells, the cell proliferation, cell cycle, apoptosis and invasion were subsequently investigated by CCK-8 assay, EdU staining, Flow cytometry analysis and Transwell assay, respectively. We also established the xenograft model to detect the effect of miR-195-5p on tumor growth and GFRA4 and p-RET expressions. GFRA4 expression was significantly downregulated in the HSCR colon tissues when compared with that in the control tissues. Overexpression of GFRA4 significantly promoted proliferation, invasion and cell cycle arrest, and inhibited apoptosis of SH-SY5Y cells. We also proved that GFRA4 is a direct target of miR-195-5p, and miR-195-5p inhibited proliferation, invasion, cell cycle arrest and differentiation, and accelerated apoptosis in SH-SY5Y cells which can be reversed by GFRA4 overexpression. Furthermore, we demonstrated that miR-195-5p suppressed tumor growth, and observably decreased GFRA4 and p-RET expressions. Our findings suggest that miR-195-5p plays an important role in the pathogenesis of HSCR. MiR-195-5p inhibited proliferation, invasion and cell cycle arrest, and accelerated apoptosis of nerve cells by targeting GFRA4.
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Affiliation(s)
- Gang Wang
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, 250021, Shandong, China.
| | - Hefeng Wang
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, 250021, Shandong, China
| | - Lijuan Zhang
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, 250021, Shandong, China
| | - Feng Guo
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, 250021, Shandong, China
| | - Xiangyu Wu
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, 250021, Shandong, China
| | - Yang Liu
- Department of Pediatric Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, No. 324, Jingwu Road, Huaiyin District, Jinan, 250021, Shandong, China
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14
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Hirschsprung Disease - Clinical Relevance of RET Mutations. Z Geburtshilfe Neonatol 2020; 225:80-82. [PMID: 32942321 DOI: 10.1055/a-1230-4045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Introduction To date, several genes involved in the pathogenesis of HD have been recognized. Out of these, the RET gene (chromosomal locus 10q11), one of the first genes identified in combination with HD, is still considered the basis for HD development. However, even with over a hundred RET gen coding sequence mutations identified, the mutations do not fully explain the observed sex bias of HD and the elevated risk of developing HD among siblings. Thus, our aim was to evaluate the clinical relevance of an as yet undescribed genotype in a family with HD to improve genetic counseling for families with RET mutation-associated HD.Patients This case report provides an overview of a family with a history of HD with a novel, unreported autosomal dominant RET mutation.Results/Summary The family examined in this study clearly demonstrates that (1) the genotype to phenotype correlation of patients with RET mutation-associated HD is not directly related, and (2) genetic mechanisms underlying the different HD phenotypes, as well as the model of inheritance of HD, are complex and not yet fully understood. As such, a multifactorial genesis of HD appears more likely and should be the center of genetic counseling for concerned families. Having identified another RET mutation with a possible correlation of severity of HD and gender will aid in filling the gaps of the incomplete picture of the pathogenesis of HD.Beim Morbus Hirschsprung handelt es sich um eine angeborene Aganglionose des Darms mit multifaktorieller Vererbung. Das RET-Protoonkogen (chromosomaler Locus 10q11), eines der ersten Gene, die in Kombination mit Morbus Hirschsprung identifiziert wurden, spielt dabei eine zentrale Rolle. Es wurden bereits über hundert Mutationen der RET-Gen-Codierungssequenz beschrieben. Vollständig verstanden ist jedoch weder das Wiederholungsrisiko noch die geschlechtsspezifische Ausprägung des Phänotyps. Vorgestellt wird eine Familie mit einer familiären Form eines Morbus Hirschsprung. Alle betroffenen Familienmitglieder weisen eine heterozygote Deletion c.1384_1410del (p.Ser462_THr470del) einer bisher in der Literatur noch nicht beschriebenen autosomal dominanten RET-Mutation auf. Die männlichen Betroffenen zeigen phänotypisch einen langstreckigen Morbus Hirschsprung, wohingegen bei den weiblichen betroffenen Familienmitgliedern lediglich das Rektosigmoid von der Aganglionose betroffen ist. Die untersuchte Familie ist ein erneuter Beweis für (1) die geringe Genotyp-Phänotyp-Korrelation von Patienten mit RET-assoziiertem Morbus Hirschsprung und (2) die komplexen genetischen Mechanismen, die dem Ausprägungsgrad von Morbus Hirschsprung zugrunde liegen.
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15
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Takahashi M, Kawai K, Asai N. Roles of the RET Proto-oncogene in Cancer and Development. JMA J 2020; 3:175-181. [PMID: 33150251 PMCID: PMC7590400 DOI: 10.31662/jmaj.2020-0021] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Accepted: 04/23/2020] [Indexed: 01/15/2023] Open
Abstract
RET (REarranged during Transfection)is activated by DNA rearrangement of the 3' fragment of the receptor tyrosine kinase gene, namely, RET proto-oncogene, with the 5' fragment of various genes with putative dimerization domains, such as a coiled coil domain, that are necessary for constitutive activation. RET rearrangements have been detected in a variety of human cancers, including thyroid, lung, colorectal, breast, and salivary gland cancers. Moreover, point mutations in RET are responsible for multiple endocrine neoplasia types 2A and 2B, which can develop into medullary thyroid cancer and pheochromocytoma. Substantial effort is currently being exerted in developing RET kinase inhibitors. RET is also responsible for Hirschsprung's disease, a developmental abnormality in the enteric nervous system. Gene knockout studies have demonstrated that RET plays essential roles in the development of the enteric nervous system and kidney as well as in spermatogenesis. Studies regarding RET continue to provide fascinating challenges in the fields of cancer research, neuroscience, and developmental biology.
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Affiliation(s)
- Masahide Takahashi
- Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan.,International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan
| | - Kumi Kawai
- Department of Pathology, Fujita Health University, Toyoake, Japan
| | - Naoya Asai
- Department of Pathology, Fujita Health University, Toyoake, Japan
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16
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Kyrklund K, Sloots CEJ, de Blaauw I, Bjørnland K, Rolle U, Cavalieri D, Francalanci P, Fusaro F, Lemli A, Schwarzer N, Fascetti-Leon F, Thapar N, Johansen LS, Berrebi D, Hugot JP, Crétolle C, Brooks AS, Hofstra RM, Wester T, Pakarinen MP. ERNICA guidelines for the management of rectosigmoid Hirschsprung's disease. Orphanet J Rare Dis 2020; 15:164. [PMID: 32586397 PMCID: PMC7318734 DOI: 10.1186/s13023-020-01362-3] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 03/18/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Hirschsprung's disease (HSCR) is a serious congenital bowel disorder with a prevalence of 1/5000. Currently, there is a lack of systematically developed guidelines to assist clinical decision-making regarding diagnostics and management. AIMS This guideline aims to cover the diagnostics and management of rectosigmoid HSCR up to adulthood. It aims to describe the preferred approach of ERNICA, the European Reference Network for rare inherited and congenital digestive disorders. METHODS Recommendations within key topics covering the care pathway for rectosigmoid HSCR were developed by an international workgroup of experts from 8 European countries within ERNICA European Reference Network from the disciplines of surgery, medicine, histopathology, microbiology, genetics, and patient organization representatives. Recommendation statements were based on a comprehensive review of the available literature and expert consensus. AGREE II and GRADE approaches were used during development. Evidence levels and levels of agreement are noted. RESULTS Thirty-three statements within 9 key areas were generated. Most recommendations were based on expert opinion. CONCLUSION In rare or low-prevalence diseases such as HSCR, there remains limited availability of high-quality clinical evidence. Consensus-based guidelines for care are presented.
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Affiliation(s)
- Kristiina Kyrklund
- Department of Pediatric Surgery, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
| | - Cornelius E J Sloots
- Department of Pediatric Surgery, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands
| | - Ivo de Blaauw
- Department of Surgery, Division of Pediatric Surgery, Radboudumc-Amalia Children's Hospital, Nijmegen, The Netherlands
| | - Kristin Bjørnland
- Department of Pediatric Surgery, Oslo University Hospital and University of Oslo, Oslo, Norway
| | - Udo Rolle
- Department of Pediatric Surgery and Pediatric Urology, University Hospital Frankfurt, Frankfurt/M, Germany
| | - Duccio Cavalieri
- Department of Biology, University of Florence, A.Mor.Hi, The Italian Association for Hirschsprung's disease, Florence, Italy
| | - Paola Francalanci
- Pathology Unit, Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Fabio Fusaro
- Neonatal Surgery Unit - Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, IRCSS, Rome, Italy
| | - Annette Lemli
- SoMA, The German patient support organization for anorectal malformations and Hirschsprung Disease, Munich, Germany
| | - Nicole Schwarzer
- SoMA, The German patient support organization for anorectal malformations and Hirschsprung Disease, Munich, Germany
| | - Francesco Fascetti-Leon
- Pediatric Surgery, Department of Women's and Children's Health, University Hospital of Padua, Padua, Italy
| | - Nikhil Thapar
- UCL Great Ormond Street Institute of Child Health; Department of Pediatric Gastroenterology, Great Ormond Street Hospital for Children, London, UK
| | | | - Dominique Berrebi
- Department of Pediatric Pathology, Hôpital Universitaire Robert Debré, Paris Diderot University, Paris, France
| | - Jean-Pierre Hugot
- Department of Pediatric Gastroenterology, Hôpital Universitaire Robert Debré, Assistance Publique Hôpitaux de Paris, Université de Paris, Paris, France
| | - Célia Crétolle
- Department of Pediatric Surgery, University Hospital Necker-Enfants Malades, APHP centre, Paris University, Paris, France
| | - Alice S Brooks
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Robert M Hofstra
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Tomas Wester
- Department of Pediatric Surgery, Karolinska University Hospital, Stockholm, Sweden
| | - Mikko P Pakarinen
- Department of Pediatric Surgery, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
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17
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Jiang Q, Wang Y, Li Q, Zhang Z, Xiao P, Wang H, Liu N, Wu J, Zhang F, Chakravarti A, Cai W, Li L. Sequence characterization of RET in 117 Chinese Hirschsprung disease families identifies a large burden of de novo and parental mosaic mutations. Orphanet J Rare Dis 2019; 14:237. [PMID: 31666091 PMCID: PMC6822467 DOI: 10.1186/s13023-019-1194-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 09/04/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by the absence of enteric ganglia in the distal part of the gut. RET is the major causative gene and contains > 80% of all known disease-causing mutations. RESULTS To determine the incidence of RET pathogenic variants, be they Mendelian inherited, mosaic in parents or true de novo variants (DNVs) in 117 Chinese families, we used high-coverage NGS and droplet digital polymerase chain reaction (ddPCR) to identify 15 (12.8%) unique RET coding variants (7 are novel); one was inherited from a heterozygous unaffected mother, 11 were DNVs (73.3%), and 3 full heterozygotes were inherited from parental mosaicism (2 paternal, 1 maternal): two clinically unaffected parents were identified by NGS and confirmed by ddPCR, with mutant allele frequency (13-27%) that was the highest in hair, lowest in urine and similar in blood and saliva. An extremely low-level paternal mosaicism (0.03%) was detected by ddPCR in blood. Six positive-controls were examined to compare the mosaicism detection limit and sensitivity of NGS, amplicon-based deep sequencing and ddPCR. CONCLUSION Our findings expand the clinical and molecular spectrum of RET variants in HSCR and reveal a high frequency of RET DNVs in the Chinese population.
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Affiliation(s)
- Qian Jiang
- Department of Medical Genetics, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Yang Wang
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, No. 1665 Kongjiang Rd., Yangpu District, Shanghai, 200092, China
| | - Qi Li
- Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, No. 2 Yabao Rd., Chaoyang District, Beijing, 100020, China
| | - Zhen Zhang
- Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, No. 2 Yabao Rd., Chaoyang District, Beijing, 100020, China
| | - Ping Xiao
- Department of Pathology, Capital Institute of Pediatrics Affiliated Children's Hospital, Beijing, 100020, China
| | - Hui Wang
- Department of Medical Genetics, Beijing Municipal Key Laboratory of Child Development and Nutriomics, Capital Institute of Pediatrics, Beijing, 100020, China
| | - Na Liu
- MyGenostics Inc, Beijing, 101318, China
| | - Jian Wu
- MyGenostics Inc, Beijing, 101318, China
| | - Feng Zhang
- Obstetrics and Gynecology Hospital, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, 200011, China
| | - Aravinda Chakravarti
- Center for Human Genetics and Genomics, New York University School of Medicine, New York, NY, 10016, USA
| | - Wei Cai
- Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai Institute for Pediatric Research, No. 1665 Kongjiang Rd., Yangpu District, Shanghai, 200092, China.
| | - Long Li
- Department of General Surgery, Capital Institute of Pediatrics Affiliated Children's Hospital, No. 2 Yabao Rd., Chaoyang District, Beijing, 100020, China.
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Luzón‐Toro B, Villalba‐Benito L, Torroglosa A, Fernández RM, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clin Genet 2019; 97:114-124. [DOI: 10.1111/cge.13615] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Revised: 07/23/2019] [Accepted: 07/25/2019] [Indexed: 01/01/2023]
Affiliation(s)
- Berta Luzón‐Toro
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Leticia Villalba‐Benito
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Ana Torroglosa
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Raquel M. Fernández
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Guillermo Antiñolo
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
| | - Salud Borrego
- Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS)University Hospital Virgen del Rocío/CSIC/University of Seville Seville Spain
- Centre for Biomedical Network Research on Rare Diseases (CIBERER) Seville Spain
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Pheochromocytomas and Paragangliomas: From Genetic Diversity to Targeted Therapies. Cancers (Basel) 2019; 11:cancers11040436. [PMID: 30925729 PMCID: PMC6521122 DOI: 10.3390/cancers11040436] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 03/25/2019] [Accepted: 03/26/2019] [Indexed: 12/13/2022] Open
Abstract
Pheochromocytoma and paraganglioma (PCPGs) are rare neuroendocrine tumors that arise from the chromaffin tissue of adrenal medulla and sympathetic ganglia. Although metastatic PCPGs account for only 10% of clinical cases, morbidity and mortality are high because of the uncontrollable mass effect and catecholamine level generated by these tumors. Despite our expanding knowledge of PCPG genetics, the clinical options to effectively suppress PCPG progression remain limited. Several recent translational studies revealed that PCPGs with different molecular subtypes exhibit distinctive oncogenic pathways and spectrum of therapy resistance. This suggests that therapeutics can be adjusted based on the signature molecular and metabolic pathways of PCPGs. In this review, we summarized the latest findings on PCPG genetics, novel therapeutic targets, and perspectives for future personalized medicine.
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Sribudiani Y, Chauhan RK, Alves MM, Petrova L, Brosens E, Harrison C, Wabbersen T, de Graaf BM, Rügenbrink T, Burzynski G, Brouwer RWW, van IJcken WFJ, Maas SM, de Klein A, Osinga J, Eggen BJL, Burns AJ, Brooks AS, Shepherd IT, Hofstra RMW. Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease. Gastroenterology 2018; 155:118-129.e6. [PMID: 29601828 DOI: 10.1053/j.gastro.2018.03.034] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Revised: 02/22/2018] [Accepted: 03/19/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND & AIMS Hirschsprung disease (HSCR) is an inherited congenital disorder characterized by absence of enteric ganglia in the distal part of the gut. Variants in ret proto-oncogene (RET) have been associated with up to 50% of familial and 35% of sporadic cases. We searched for variants that affect disease risk in a large, multigenerational family with history of HSCR in a linkage region previously associated with the disease (4q31.3-q32.3) and exome wide. METHODS We performed exome sequencing analyses of a family in the Netherlands with 5 members diagnosed with HSCR and 2 members diagnosed with functional constipation. We initially focused on variants in genes located in 4q31.3-q32.3; however, we also performed an exome-wide analysis in which known HSCR or HSCR-associated gene variants predicted to be deleterious were prioritized for further analysis. Candidate genes were expressed in HEK293, COS-7, and Neuro-2a cells and analyzed by luciferase and immunoblot assays. Morpholinos were designed to target exons of candidate genes and injected into 1-cell stage zebrafish embryos. Embryos were allowed to develop and stained for enteric neurons. RESULTS Within the linkage region, we identified 1 putative splice variant in the lipopolysaccharide responsive beige-like anchor protein gene (LRBA). Functional assays could not confirm its predicted effect on messenger RNA splicing or on expression of the mab-21 like 2 gene (MAB21L2), which is embedded in LRBA. Zebrafish that developed following injection of the lrba morpholino had a shortened body axis and subtle gut morphological defects, but no significant reduction in number of enteric neurons compared with controls. Outside the linkage region, members of 1 branch of the family carried a previously unidentified RET variant or an in-frame deletion in the glial cell line derived neurotrophic factor gene (GDNF), which encodes a ligand of RET. This deletion was located 6 base pairs before the last codon. We also found variants in the Indian hedgehog gene (IHH) and its mediator, the transcription factor GLI family zinc finger 3 (GLI3). When expressed in cells, the RET-P399L variant disrupted protein glycosylation and had altered phosphorylation following activation by GDNF. The deletion in GDNF prevented secretion of its gene product, reducing RET activation, and the IHH-Q51K variant reduced expression of the transcription factor GLI1. Injection of morpholinos that target ihh reduced the number of enteric neurons to 13% ± 1.4% of control zebrafish. CONCLUSIONS In a study of a large family with history of HSCR, we identified variants in LRBA, RET, the gene encoding the RET ligand (GDNF), IHH, and a gene encoding a mediator of IHH signaling (GLI3). These variants altered functions of the gene products when expressed in cells and knockout of ihh reduced the number of enteric neurons in the zebrafish gut.
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Affiliation(s)
- Yunia Sribudiani
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; Department of Biomedical Sciences, Division of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
| | - Rajendra K Chauhan
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Maria M Alves
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Lucy Petrova
- Department of Biology, Emory University, Atlanta, Georgia
| | - Erwin Brosens
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Colin Harrison
- Department of Biology, Emory University, Atlanta, Georgia
| | - Tara Wabbersen
- Department of Biology, Emory University, Atlanta, Georgia
| | - Bianca M de Graaf
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Tim Rügenbrink
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Rutger W W Brouwer
- Erasmus Center for Biomics, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Saskia M Maas
- Department of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Annelies de Klein
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Jan Osinga
- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Bart J L Eggen
- Department of Neuroscience, Section Medical Physiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Alan J Burns
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; Neural Development and Gastroenterology Units, UCL Institute of Child Health, London, UK
| | - Alice S Brooks
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Robert M W Hofstra
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands; Neural Development and Gastroenterology Units, UCL Institute of Child Health, London, UK.
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Hirschsprung disease - integrating basic science and clinical medicine to improve outcomes. Nat Rev Gastroenterol Hepatol 2018; 15:152-167. [PMID: 29300049 DOI: 10.1038/nrgastro.2017.149] [Citation(s) in RCA: 179] [Impact Index Per Article: 25.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hirschsprung disease is defined by the absence of enteric neurons at the end of the bowel. The enteric nervous system (ENS) is the intrinsic nervous system of the bowel and regulates most aspects of bowel function. When the ENS is missing, there are no neurally mediated propulsive motility patterns, and the bowel remains contracted, causing functional obstruction. Symptoms of Hirschsprung disease include constipation, vomiting, abdominal distension and growth failure. Untreated disease usually causes death in childhood because bloodstream bacterial infections occur in the context of bowel inflammation (enterocolitis) or bowel perforation. Current treatment is surgical resection of the bowel to remove or bypass regions where the ENS is missing, but many children have problems after surgery. Although the anatomy of Hirschsprung disease is simple, many clinical features remain enigmatic, and diagnosis and management remain challenging. For example, the age of presentation and the type of symptoms that occur vary dramatically among patients, even though every affected child has missing neurons in the distal bowel at birth. In this Review, basic science discoveries are linked to clinical manifestations of Hirschsprung disease, including partial penetrance, enterocolitis and genetics. Insights into disease mechanisms that might lead to new prevention, diagnostic and treatment strategies are described.
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22
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Paragliola RM, Lovicu RM, Papi G, Capoluongo E, Minucci A, Canu G, Pontecorvi A, Corsello SM. Medullary Thyroid Carcinoma With Exon 2 p.L56M RET Variant: Clinical Particular Features in Two Patients. Front Endocrinol (Lausanne) 2018; 9:398. [PMID: 30072953 PMCID: PMC6060540 DOI: 10.3389/fendo.2018.00398] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 06/27/2018] [Indexed: 11/25/2022] Open
Abstract
RET (REarranged during Transfection) proto-oncogene variants are essential for the development of familial and sporadic forms of medullary thyroid carcinoma (MTC). The most frequent variants are usually located in exons 10, 11, and 13 through 16 of the RET gene. We report two cases of apparently sporadic MTC associated with the variant in exon 2 of RET gene. Patient 1, a 62-year old man who had undergone adrenalectomy for a 5 cm pheochromocytoma, was screened for type 2 multiple endocrine neoplasia (MEN 2) which showed elevated basal and post-intravenous calcium gluconate calcitonin levels. A fine needle aspiration biopsy (FNAB) confirmed the suspicion of MTC. The patient underwent total thyroidectomy and lymphadenectomy, and the histology showed C-cell hyperplasia with medullary microcarcinoma. Patient 2, a 57 years old woman, underwent total thyroidectomy for toxic multinodular goiter. Pre-operative FNAB had shown benign features, while basal calcitonin levels were only borderline increased. Final histology revealed medullary multifocal microcarcinoma. Genetic testing for RET protoncogene on DNA extracted from peripheral blood was performed in both patients and a missense variant on exon 2 (c.166C>A, p.L56M) was identified. To our knowledge, these are the first time two cases of MTC associated to RET p.L56M variant. Interestingly, one patient had also a pheochromocytoma suggesting a possible pathogenetic role of this variant in the genesis of MEN2A. While the association of this variant with MTC or MEN2A has been never reported, it has been described in association with Hirschsprung's disease.
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Affiliation(s)
- Rosa M. Paragliola
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Rosa M. Lovicu
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giampaolo Papi
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ettore Capoluongo
- Unit of Biochemistry and Clinical Biochemistry, F. Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Angelo Minucci
- Unit of Biochemistry and Clinical Biochemistry, F. Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giulia Canu
- Unit of Biochemistry and Clinical Biochemistry, F. Policlinico Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Alfredo Pontecorvi
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Salvatore M. Corsello
- Unit of Endocrinology, Università Cattolica del Sacro Cuore, Rome, Italy
- *Correspondence: Salvatore M. Corsello
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23
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Metzger R. Morbus Hirschsprung. Monatsschr Kinderheilkd 2017. [DOI: 10.1007/s00112-017-0250-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Regulators of gene expression in Enteric Neural Crest Cells are putative Hirschsprung disease genes. Dev Biol 2016; 416:255-265. [DOI: 10.1016/j.ydbio.2016.06.004] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 05/17/2016] [Accepted: 06/02/2016] [Indexed: 11/21/2022]
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25
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Bondurand N, Southard-Smith EM. Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players. Dev Biol 2016; 417:139-57. [PMID: 27370713 DOI: 10.1016/j.ydbio.2016.06.042] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2016] [Revised: 06/27/2016] [Accepted: 06/27/2016] [Indexed: 12/18/2022]
Abstract
Hirschsprung disease (HSCR, intestinal aganglionosis) is a multigenic disorder with variable penetrance and severity that has a general population incidence of 1/5000 live births. Studies using animal models have contributed to our understanding of the developmental origins of HSCR and the genetic complexity of this disease. This review summarizes recent progress in understanding control of enteric nervous system (ENS) development through analyses in mouse models. An overview of signaling pathways that have long been known to control the migration, proliferation and differentiation of enteric neural progenitors into and along the developing gut is provided as a framework for the latest information on factors that influence enteric ganglia formation and maintenance. Newly identified genes and additional factors beyond discrete genes that contribute to ENS pathology including regulatory sequences, miRNAs and environmental factors are also introduced. Finally, because HSCR has become a paradigm for complex oligogenic diseases with non-Mendelian inheritance, the importance of gene interactions, modifier genes, and initial studies on genetic background effects are outlined.
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Affiliation(s)
- Nadege Bondurand
- INSERM, U955, Equipe 6, F-94000 Creteil, France; Universite Paris-Est, UPEC, F-94000 Creteil, France.
| | - E Michelle Southard-Smith
- Vanderbilt University Medical Center, Department of Medicine, 2215 Garland Ave, Nashville, TN 37232, USA.
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26
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Burns AJ, Goldstein AM, Newgreen DF, Stamp L, Schäfer KH, Metzger M, Hotta R, Young HM, Andrews PW, Thapar N, Belkind-Gerson J, Bondurand N, Bornstein JC, Chan WY, Cheah K, Gershon MD, Heuckeroth RO, Hofstra RMW, Just L, Kapur RP, King SK, McCann CJ, Nagy N, Ngan E, Obermayr F, Pachnis V, Pasricha PJ, Sham MH, Tam P, Vanden Berghe P. White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies. Dev Biol 2016; 417:229-51. [PMID: 27059883 DOI: 10.1016/j.ydbio.2016.04.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 03/29/2016] [Accepted: 04/02/2016] [Indexed: 12/22/2022]
Abstract
Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts' views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.
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Affiliation(s)
- Alan J Burns
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands.
| | - Allan M Goldstein
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Donald F Newgreen
- Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville 3052, Victoria, Australia
| | - Lincon Stamp
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Karl-Herbert Schäfer
- University of Applied Sciences, Kaiserlautern, Germany; Clinic of Pediatric Surgery, University Hospital Mannheim, University Heidelberg, Germany
| | - Marco Metzger
- Fraunhofer-Institute Interfacial Engineering and Biotechnology IGB Translational Centre - Würzburg branch and University Hospital Würzburg - Tissue Engineering and Regenerative Medicine (TERM), Würzburg, Germany
| | - Ryo Hotta
- Department of Pediatric Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Heather M Young
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Peter W Andrews
- Centre for Stem Cell Biology, Department of Biomedical Science, University of Sheffield, Sheffield, UK
| | - Nikhil Thapar
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Jaime Belkind-Gerson
- Division of Gastroenterology, Hepatology and Nutrition, Massachusetts General Hospital for Children, Harvard Medical School, Boston, USA
| | - Nadege Bondurand
- INSERM U955, 51 Avenue du Maréchal de Lattre de Tassigny, F-94000 Créteil, France; Université Paris-Est, UPEC, F-94000 Créteil, France
| | - Joel C Bornstein
- Department of Physiology, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Wood Yee Chan
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong
| | - Kathryn Cheah
- School of Biomedical Sciences, The University of Hong Kong, Hong Kong
| | - Michael D Gershon
- Department of Pathology and Cell Biology, Columbia University, New York 10032, USA
| | - Robert O Heuckeroth
- Department of Pediatrics, The Children's Hospital of Philadelphia Research Institute, Philadelphia, PA 19104, USA; Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA 19104, USA
| | - Robert M W Hofstra
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK; Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Lothar Just
- Institute of Clinical Anatomy and Cell Analysis, University of Tübingen, Germany
| | - Raj P Kapur
- Department of Pathology, University of Washington and Seattle Children's Hospital, Seattle, WA, USA
| | - Sebastian K King
- Department of Paediatric and Neonatal Surgery, The Royal Children's Hospital, Melbourne, Australia
| | - Conor J McCann
- Stem Cells and Regenerative Medicine, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Nandor Nagy
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Elly Ngan
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Florian Obermayr
- Department of Pediatric Surgery and Pediatric Urology, University Children's Hospital Tübingen, D-72076 Tübingen, Germany
| | | | | | - Mai Har Sham
- Department of Biochemistry, The University of Hong Kong, Hong Kong
| | - Paul Tam
- Department of Surgery, The University of Hong Kong, Hong Kong
| | - Pieter Vanden Berghe
- Laboratory for Enteric NeuroScience (LENS), TARGID, University of Leuven, Belgium
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Abstract
PURPOSE Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder, which is caused by no neuronal ganglion cells in part or all of distal gastrointestinal tract. Recently, our genome-wide association study has identified solute carrier family 6, proline IMINO transporter, member 20 (SLC6A20) as one of the potential risk factors for HSCR development. This study performed a replication study for the association of SLC6A20 polymorphisms with HSCR and an extended analysis to investigate further associations for subgroups and haplotypes. METHODS For the replication study, a total of 40 single nucleotide polymorphisms (SNPs) of SLC6A20 were genotyped in 187 HSCR subjects composed of 121 short-segment HSCR, 45 long-segment HSCR (L-HSCR), 21 total colonic aganglionosis, and 283 unaffected controls. Imputation was performed using genotype data from our genome-wide association study and this replication study. RESULTS Imputed meta-analysis revealed that 13 SLC6A20 SNPs (minimum P = 0.0002 at rs6770261) were significantly associated with HSCR even after correction for multiple comparisons using false discovery rate (FDR) (minimum PFDR = .005). In further subgroup analysis, SLC6A20 polymorphisms appeared to have increased associations with L-HSCR. Moreover, haplotype analysis also showed significant associations between 2 haplotypes (BL3_ht2 and BL4_ht2) and HSCR susceptibility (PFDR < .05). CONCLUSIONS Although further replications and functional evaluations are required, our results suggest that SLC6A20 may have roles in HSCR development and in the extent of aganglionic segment during enteric nervous system development.
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Widowati T, Melhem S, Patria SY, de Graaf BM, Sinke RJ, Viel M, Dijkhuis J, Sadewa AH, Purwohardjono R, Soenarto Y, Hofstra RM, Sribudiani Y. RET and EDNRB mutation screening in patients with Hirschsprung disease: Functional studies and its implications for genetic counseling. Eur J Hum Genet 2015; 24:823-9. [PMID: 26395553 DOI: 10.1038/ejhg.2015.214] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2015] [Revised: 08/24/2015] [Accepted: 08/27/2015] [Indexed: 12/22/2022] Open
Abstract
Hirschsprung disease (HSCR) is a major cause of chronic constipation in children. HSCR can be caused by germline mutations in RET and EDNRB. Defining causality of the mutations identified is difficult and almost exclusively based on in silico predictions. Therefore, the reported frequency of pathogenic mutations might be overestimated. We combined mutation analysis with functional assays to determine the frequencies of proven pathogenic RET and EDNRB mutations in HSCR. We sequenced RET and EDNRB in 57 HSCR patients. The identified RET-coding variants were introduced into RET constructs and these were transfected into HEK293 cells to determine RET phosphorylation and activation via ERK. An exon trap experiment was performed to check a possible splice-site mutation. We identified eight rare RET-coding variants, one possible splice-site variant, but no rare EDNRB variants. Western blotting showed that three coding variants p.(Pr270Leu), p.(Ala756Val) and p.(Tyr1062Cys) resulted in lower activation of RET. Moreover, only two RET variants (p.(Ala756Val) and p.(Tyr1062Cys)) resulted in reduced ERK activation. Splice-site assays on c.1880-11A>G could not confirm its pathogenicity. Our data suggest that indeed almost half of the identified rare variants are proven pathogenic and that, hence, functional studies are essential for proper genetic counseling.
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Affiliation(s)
- Titis Widowati
- Department of Pediatric, Faculty of Medicine, Universitas Gadjah Mada, Prof.Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Shamiram Melhem
- Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Suryono Y Patria
- Department of Pediatric, Faculty of Medicine, Universitas Gadjah Mada, Prof.Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Bianca M de Graaf
- Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Richard J Sinke
- Department of Genetic, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Martijn Viel
- Department of Genetic, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jos Dijkhuis
- Department of Genetic, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Ahmad H Sadewa
- Department of Biochemistry, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Rochadi Purwohardjono
- Department of Pediatric Surgery, Faculty of Medicine, Universitas Gadjah Mada, Prof.Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Yati Soenarto
- Department of Pediatric, Faculty of Medicine, Universitas Gadjah Mada, Prof.Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Robert Mw Hofstra
- Department of Clinical Genetic, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Yunia Sribudiani
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia
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Huang J, Dang R, Torigoe D, Li A, Lei C, Sasaki N, Wang J, Agui T. Genetic variation in the GDNF promoter affects its expression and modifies the severity of Hirschsprung's disease (HSCR) in rats carrying Ednrb(sl) mutations. Gene 2015; 575:144-8. [PMID: 26318480 DOI: 10.1016/j.gene.2015.08.051] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Revised: 08/12/2015] [Accepted: 08/24/2015] [Indexed: 12/20/2022]
Abstract
Glial cell line-derived neurotrophic factor (GDNF) is necessary for the migration of neural crest stem cells in the gut. However, mutations in GDNF per se are deemed neither necessary nor sufficient to cause Hirschsprung's disease (HSCR). In a previous study, a modifier locus on chromosome 2 in rats carrying Ednrb(sl) mutations was identified, and several mutations in the putative regulatory region of the Gdnf gene in AGH-Ednrb(sl) rats were detected. Specifically, the mutation -232C>T has been shown to be strongly associated with the severity of HSCR. In the present study, the influence of genetic variations on the transcription of the Gdnf gene was tested using dual-luciferase assay. Results showed that the mutation -613C>T, located near the mutation -232C>T in AGH-Ednrb(sl) rats, decreased Gdnf transcription in an in vitro dual-luciferase expression assay. These data suggested an important role of -613C in Gdnf transcription. Expression levels of the Gdnf gene may modify the severity of HSCR in rats carrying Ednrb(sl) mutations.
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Affiliation(s)
- Jieping Huang
- College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, China; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Ruihua Dang
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
| | - Daisuke Torigoe
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan; Division of Microbiology and Genetics, Center for Animal Resources and Development, Kumamoto, Japan
| | - Anqi Li
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China
| | - Chuzhao Lei
- College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
| | - Nobuya Sasaki
- Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Aomori, Japan
| | - Jinxi Wang
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
| | - Takashi Agui
- Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan
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Abstract
PURPOSE During the past two decades several genes have been identified that control morphogenesis and differentiation of the enteric neuron system (ENS). These genes, when mutated or deleted, interfere with ENS development. RET gene is the major gene causing Hirschsprung's disease (HD). Mutations in RET gene are responsible for 50% of familial HD cases and 15-20% of sporadic cases. The aim of this meta-analysis was to determine the incidence of RET gene mutations in patients with HD and to correlate RET mutations with the extent of aganglionosis. METHODS A systematic literature-based search for relevant cohorts was performed using the terms "Hirschsprung's disease AND RET Proto-oncogene", "Hirschsprung's disease AND genetic polymorphism" and "RET Gene". The relevant cohorts of HD were systematically searched for reported mutations in the RET gene (RET+). Data on mutation site, phenotype, and familial or sporadic cases were extracted. Combined odds ratio (OR) with 95% CI was calculated to estimate the strength of the different associations. RESULTS In total, 23 studies concerning RET with 1270 individuals affected with HD were included in this study. 228 (18%) of these HDs were RET+. Of these 228, 96 (42%) presented as rectosigmoid, 81 (36%) long segment, 18 (8%) as TCA, 16 (7%) as total intestinal aganglionosis and 17 (7%) individuals were RET+ but no extent of aganglionosis was not reported. In the rectosigmoid group, no significant association between phenotype and RET mutation could be shown (P = 0.006), whereas a clear association could be shown between long-segment disease, total colonic- and total intestinal aganglionosis and RET mutations (P = 0.0002). Mutations most often occurred in Exon 13 (24) and showed significant association with rectosigmoid disease (P = 0.004). No significance could be shown between RET+ and sporadic cases (P = 0.53), albeit a trend towards RET+ and Familial cases could be observed (P = 0.38). CONCLUSIONS The association with the RET gene and HD is well recognized. This study showed a clear association between RET+ mutations and the long-segment, total colonic- and total intestinal aganglionosis. Exon 13 appears to be a mutational "hot spot" in rectosigmoid disease.
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Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, Lee N, Machens A, Moley JF, Pacini F, Raue F, Frank-Raue K, Robinson B, Rosenthal MS, Santoro M, Schlumberger M, Shah M, Waguespack SG. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 2015; 25:567-610. [PMID: 25810047 PMCID: PMC4490627 DOI: 10.1089/thy.2014.0335] [Citation(s) in RCA: 1442] [Impact Index Per Article: 144.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
INTRODUCTION The American Thyroid Association appointed a Task Force of experts to revise the original Medullary Thyroid Carcinoma: Management Guidelines of the American Thyroid Association. METHODS The Task Force identified relevant articles using a systematic PubMed search, supplemented with additional published materials, and then created evidence-based recommendations, which were set in categories using criteria adapted from the United States Preventive Services Task Force Agency for Healthcare Research and Quality. The original guidelines provided abundant source material and an excellent organizational structure that served as the basis for the current revised document. RESULTS The revised guidelines are focused primarily on the diagnosis and treatment of patients with sporadic medullary thyroid carcinoma (MTC) and hereditary MTC. CONCLUSIONS The Task Force developed 67 evidence-based recommendations to assist clinicians in the care of patients with MTC. The Task Force considers the recommendations to represent current, rational, and optimal medical practice.
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Affiliation(s)
- Samuel A. Wells
- Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sylvia L. Asa
- Department of Pathology, University Health Network, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Henning Dralle
- Department of General, Visceral, and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany
| | - Rossella Elisei
- Department of Endocrinology, University of Pisa, Pisa, Italy
| | - Douglas B. Evans
- Department of Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Robert F. Gagel
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nancy Lee
- Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Andreas Machens
- Department of General, Visceral, and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, Germany
| | - Jeffrey F. Moley
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Furio Pacini
- Section of Endocrinology and Metabolism, Department of Internal Medicine, Endocrinology and Metabolism and Biochemistry, University of Siena, Policlinico Santa Maria alle Scotte, Siena, Italy
| | - Friedhelm Raue
- Endocrine Practice, Moleculargenetic Laboratory, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Karin Frank-Raue
- Endocrine Practice, Moleculargenetic Laboratory, Medical Faculty, University of Heidelberg, Heidelberg, Germany
| | - Bruce Robinson
- University of Sydney School of Medicine, Sydney, New South Wales, Australia
| | - M. Sara Rosenthal
- Departments of Internal Medicine, Pediatrics and Behavioral Science, University of Kentucky, Lexington, Kentucky
| | - Massimo Santoro
- Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita' di Napoli “Federico II,” Napoli, Italy
| | - Martin Schlumberger
- Institut Gustave Roussy, Service de Medecine Nucleaire, Université of Paris-Sud, Villejuif, France
| | - Manisha Shah
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Steven G. Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Buchner DA, Nadeau JH. Contrasting genetic architectures in different mouse reference populations used for studying complex traits. Genome Res 2015; 25:775-91. [PMID: 25953951 PMCID: PMC4448675 DOI: 10.1101/gr.187450.114] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 03/31/2015] [Indexed: 01/14/2023]
Abstract
Quantitative trait loci (QTLs) are being used to study genetic networks, protein functions, and systems properties that underlie phenotypic variation and disease risk in humans, model organisms, agricultural species, and natural populations. The challenges are many, beginning with the seemingly simple tasks of mapping QTLs and identifying their underlying genetic determinants. Various specialized resources have been developed to study complex traits in many model organisms. In the mouse, remarkably different pictures of genetic architectures are emerging. Chromosome Substitution Strains (CSSs) reveal many QTLs, large phenotypic effects, pervasive epistasis, and readily identified genetic variants. In contrast, other resources as well as genome-wide association studies (GWAS) in humans and other species reveal genetic architectures dominated with a relatively modest number of QTLs that have small individual and combined phenotypic effects. These contrasting architectures are the result of intrinsic differences in the study designs underlying different resources. The CSSs examine context-dependent phenotypic effects independently among individual genotypes, whereas with GWAS and other mouse resources, the average effect of each QTL is assessed among many individuals with heterogeneous genetic backgrounds. We argue that variation of genetic architectures among individuals is as important as population averages. Each of these important resources has particular merits and specific applications for these individual and population perspectives. Collectively, these resources together with high-throughput genotyping, sequencing and genetic engineering technologies, and information repositories highlight the power of the mouse for genetic, functional, and systems studies of complex traits and disease models.
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Affiliation(s)
- David A Buchner
- Department of Genetics and Genome Sciences, Department of Biochemistry, Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Joseph H Nadeau
- Pacific Northwest Diabetes Research Institute, Seattle, Washington 98122, USA
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Moore SW, Zaahl M. Clinical and genetic correlations of familial Hirschsprung's disease. J Pediatr Surg 2015; 50:285-8. [PMID: 25638620 DOI: 10.1016/j.jpedsurg.2014.11.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 11/02/2014] [Indexed: 02/04/2023]
Abstract
BACKGROUND The risk of familial transmission in Hirschsprung's disease (HSCR) currently lacks correlation between the clinical phenotype and the underlying genetic factors. The aim of this study was to clinically evaluate familial HSCR transmission and to correlate with the genetic background. METHODS Clinical and gene analysis of familial HSCR patients were explored. DNA from 45 patients (35 kindreds) was screened for genetic variations of the RET, and EDNRB genes were screened for genetic variation by semi-automated bi-directional sequencing analysis and matched to controls. MAIN RESULTS Male:female ratio (3:1) had a female proband in 4 families. Aganglionosis was significantly more frequent with total colonic aganglionosis (TCA) in 40% familial cases (viz: 17/43 (43%) vs. 19/342 non-familial patients (5.6%) (p<0.01)). Transmission of S-HSCR was observed in 13 (31%), which was associated with EDNRB variation. RET gene promoter variation correlated with extended aganglionosis in 6/35 kindreds (17%). In 3 kindreds, both significant EDNRB and RET mutations were identified and where present were associated with increased penetrance in succeeding generations. An increased penetrance with succeeding generations occurred in 6 (14%). In a further 3 generation family, extensive variations in exon 6, 13, and 18 affected 3 males with progressive penetration and aganglionic length, including total intestinal aganglionosis in the further offspring. RET and MEN association was noted in 5 kindreds (14.3%) related to RET variations at Cysteine sites. CONCLUSIONS Cumulative effects of the RET and EDNRB genes contribute to long-segment and total colonic aganglionosis.
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Affiliation(s)
- Sam W Moore
- Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape, South Africa.
| | - Monique Zaahl
- Division of Paediatric Surgery, University of Stellenbosch, Tygerberg, Western Cape, South Africa
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Hibi Y, Ohye T, Ogawa K, Shimizu Y, Shibata M, Kagawa C, Mizuno Y, Kurahashi H, Iwase K. A MEN2A family with two asymptomatic carriers affected by unilateral renal agenesis. Endocr J 2014; 61:19-23. [PMID: 24152999 DOI: 10.1507/endocrj.ej13-0335] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Accumulating evidences suggest RET gene's involvement in development of the kidney in mice and humans. Although it is well known that RET mutation causes multiple endocrine neoplasia type 2A (MEN2A), thus far only 3 individuals have been reported to have MEN2A and renal agenesis/dysgenesis. We report a MEN2A family with RET mutation in which two asymptomatic carriers presented with unilateral renal agenesis. A 48-year-old woman underwent total thyroidectomy with regional lymph node dissection in our department for medullary thyroid carcinoma. She had earlier surgical treatment for a left adrenal pheochromocytoma at the age of 45. In the screening for MEN type 2 for her three sons, a CT scan for adrenal pheochromocytoma incidentally found unilateral renal agenesis in two of the sons, one of whom had suffered from Hirschsprung's disease (HSCR). They had contralateral kidneys exhibiting compensatory hypertrophy and normal renal function. Genetic analysis detected C618R RET mutation in the proband and her 3 sons, and no other mutations were found in RET as well as glial cell line-derived neurotrophic factor (GDNF). Our data lend support to the hypothesis that constitutive active RET mutation in MEN type 2 might partially impair RET function and thereby cause loss of function phenotype such as renal agenesis or HSCR.
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Affiliation(s)
- Yatsuka Hibi
- Department of Endocrine Surgery, Fujita Health University School of Medicine, Toyoake 470-1192, Japan
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Homozygous truncating mutation of the KBP gene, encoding a KIF1B-binding protein, in a familial case of fetal polymicrogyria. Neurogenetics 2013; 14:215-24. [DOI: 10.1007/s10048-013-0373-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2013] [Accepted: 08/28/2013] [Indexed: 01/12/2023]
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Virtanen VB, Pukkala E, Kivisaari R, Salo PP, Koivusalo A, Arola J, Miettinen PJ, Rintala RJ, Perola M, Pakarinen MP. Thyroid cancer and co-occurring RET mutations in Hirschsprung disease. Endocr Relat Cancer 2013; 20:595-602. [PMID: 23744765 DOI: 10.1530/erc-13-0082] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The objective of this study was to assess the occurrence of thyroid cancer and co-occurring RET mutations in a population-based cohort of adult Hirschsprung disease (HD) patients. All 156 patients operated for HD in a tertiary center during 1950-1986 were followed for thyroid malignancies up to 2010 through the nationwide Finnish Cancer Registry. Ninety-one individuals participated in clinical and genetic screening, which included serum calcitonin and thyroid ultrasound (US) with cytology. Exons 10, 11, 13, and 16 were sequenced in all, and all exons of RET in 43 of the subjects, including those with thyroid cancer, RET mutations, suspicious clinical findings, and familial or long-segment disease. Through the cancer registry, two cases (aged 35 and 37 years) of medullary thyroid cancer (MTC) were observed; the incidence for MTC was 340-fold (95% CI 52-1600) compared with average population. These individuals had C611R and C620R mutations in exon 10. One papillary thyroid cancer without RET mutations was detected by clinical screening. Four subjects (aged 31-50 years) with co-occurring RET mutations in exons 10 (C609R; n=1) and 13 (Y791F, n=3) had sporadic short-segment HD with normal thyroid US and serum calcitonin. Three novel mutations and five single-nucleotide polymorphisms were found outside exons 10 and 13 without associated signs of thyroid cancer. MTC-associated RET mutations were restricted to exons 10 and 13 affecting ∼5% of unselected adults with HD. Clinical thyroid assessment did not improve accuracy of genetic screening, which should not be limited to patients with familial or long-segment disease.
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Affiliation(s)
- Valtter B Virtanen
- Section of Pediatric Surgery, Hospital for Children and Adolescents, University of Helsinki, Stenbäckinkatu 11, Helsinki, Finland.
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Alves MM, Sribudiani Y, Brouwer RWW, Amiel J, Antiñolo G, Borrego S, Ceccherini I, Chakravarti A, Fernández RM, Garcia-Barcelo MM, Griseri P, Lyonnet S, Tam PK, van Ijcken WFJ, Eggen BJL, te Meerman GJ, Hofstra RMW. Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model. Dev Biol 2013; 382:320-9. [PMID: 23707863 DOI: 10.1016/j.ydbio.2013.05.019] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2012] [Revised: 05/13/2013] [Accepted: 05/15/2013] [Indexed: 12/22/2022]
Abstract
Finding genes for complex diseases has been the goal of many genetic studies. Most of these studies have been successful by searching for genes and mutations in rare familial cases, by screening candidate genes and by performing genome wide association studies. However, only a small fraction of the total genetic risk for these complex genetic diseases can be explained by the identified mutations and associated genetic loci. In this review we focus on Hirschsprung disease (HSCR) as an example of a complex genetic disorder. We describe the genes identified in this congenital malformation and postulate that both common 'low penetrant' variants in combination with rare or private 'high penetrant' variants determine the risk on HSCR, and likely, on other complex diseases. We also discuss how new technological advances can be used to gain further insights in the genetic background of complex diseases. Finally, we outline a few steps to develop functional assays in order to determine the involvement of these variants in disease development.
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Affiliation(s)
- Maria M Alves
- Department of Clinical Genetics, Dr. Molewaterplein, 50, Rotterdam, The Netherlands.
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Amiñoso C, García-Miñaúr S, Martínez L, Tenorio J, Tovar J, Lapunzina P, Solera J. Recurrence of Hirschsprung disease due to maternal mosaicism of a novelRETgene mutation. Clin Genet 2013; 85:401-2. [DOI: 10.1111/cge.12163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- C. Amiñoso
- Molecular Oncogenetics Section, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
- Unit 753, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Salud Carlos III; Madrid Spain
| | - S. García-Miñaúr
- Unit 753, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Salud Carlos III; Madrid Spain
- Clinical Genetics Section, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
| | - L. Martínez
- Pediatric Surgery Department, INGEMM and IdiPAZ Research Laboratory, Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
| | - J.A. Tenorio
- Molecular Oncogenetics Section, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
- Unit 753, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Salud Carlos III; Madrid Spain
| | - J.A. Tovar
- Pediatric Surgery Department, INGEMM and IdiPAZ Research Laboratory, Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
| | - P. Lapunzina
- Unit 753, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Salud Carlos III; Madrid Spain
- Clinical Genetics Section, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
| | - J. Solera
- Molecular Oncogenetics Section, Institute of Medical and Molecular Genetics (INGEMM), Hospital Universitario La Paz; Universidad Autónoma de Madrid; Madrid Spain
- Unit 753, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER); Instituto de Salud Carlos III; Madrid Spain
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Induction of RET dependent and independent pro-inflammatory programs in human peripheral blood mononuclear cells from Hirschsprung patients. PLoS One 2013; 8:e59066. [PMID: 23527089 PMCID: PMC3601093 DOI: 10.1371/journal.pone.0059066] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 02/12/2013] [Indexed: 12/22/2022] Open
Abstract
Hirschsprung disease (HSCR) is a rare congenital anomaly characterized by the absence of enteric ganglia in the distal intestinal tract. While classified as a multigenic disorder, the altered function of the RET tyrosine kinase receptor is responsible for the majority of the pathogenesis of HSCR. Recent evidence demonstrate a strong association between RET and the homeostasis of immune system. Here, we utilize a unique cohort of fifty HSCR patients to fully characterize the expression of RET receptor on both innate (monocytes and Natural Killer lymphocytes) and adaptive (B and T lymphocytes) human peripheral blood mononuclear cells (PBMCs) and to explore the role of RET signaling in the immune system. We show that the increased expression of RET receptor on immune cell subsets from HSCR individuals correlates with the presence of loss-of-function RET mutations. Moreover, we demonstrate that the engagement of RET on PBMCs induces the modulation of several inflammatory genes. In particular, RET stimulation with glial-cell line derived neurotrophic factor family (GDNF) and glycosyl-phosphatidylinositol membrane anchored co-receptor α1 (GFRα1) trigger the up-modulation of genes encoding either for chemokines (CCL20, CCL2, CCL3, CCL4, CCL7, CXCL1) and cytokines (IL-1β, IL-6 and IL-8) and the down-regulation of chemokine/cytokine receptors (CCR2 and IL8-Rα). Although at different levels, the modulation of these “RET-dependent genes” occurs in both healthy donors and HSCR patients. We also describe another set of genes that, independently from RET stimulation, are differently regulated in healthy donors versus HSCR patients. Among these “RET-independent genes”, there are CSF-1R, IL1-R1, IL1-R2 and TGFβ-1, whose levels of transcripts were lower in HSCR patients compared to healthy donors, thus suggesting aberrancies of inflammatory responses at mucosal level. Overall our results demonstrate that immune system actively participates in the physiopathology of HSCR disease by modulating inflammatory programs that are either dependent or independent from RET signaling.
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Hyndman BD, Gujral TS, Krieger JR, Cockburn JG, Mulligan LM. Multiple functional effects of RET kinase domain sequence variants in Hirschsprung disease. Hum Mutat 2012; 34:132-42. [PMID: 22837065 DOI: 10.1002/humu.22170] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Accepted: 07/16/2012] [Indexed: 01/08/2023]
Abstract
The REarranged during Transfection (RET) gene encodes a receptor tyrosine kinase required for maturation of the enteric nervous system. RET sequence variants occur in the congenital abnormality Hirschsprung disease (HSCR), characterized by absence of ganglia in the intestinal tract. Although HSCR-RET variants are predicted to inactivate RET, the molecular mechanisms of these events are not well characterized. Using structure-based models of RET, we predicted the molecular consequences of 23 HSCR-associated missense variants and how they lead to receptor dysfunction. We validated our predictions in biochemical and cell-based assays to explore mutational effects on RET protein functions. We found a minority of HSCR-RET variants abrogated RET kinase function, while the remaining mutants were phosphorylated and transduced intracellular signals. HSCR-RET sequence variants also impacted on maturation, stability, and degradation of RET proteins. We showed that each variant conferred a unique combination of effects that together impaired RET protein activity. However, all tested variants impaired RET-mediated cellular functions, including cell transformation and migration. Our data indicate that the molecular mechanisms of impaired RET function in HSCR are highly variable. Although a subset of variants cause loss of RET kinase activity and downstream signaling, enzymatic inactivation is not the sole mechanism at play in HSCR.
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Affiliation(s)
- Brandy D Hyndman
- Division of Cancer Biology and Genetics, Cancer Research Institute, and Department of Pathology and Molecular Medicine, Queen's University, Kingston, ON, Canada
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Pan ZW, Li JC. Advances in molecular genetics of Hirschsprung's disease. Anat Rec (Hoboken) 2012; 295:1628-38. [PMID: 22815266 DOI: 10.1002/ar.22538] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 06/21/2012] [Indexed: 12/23/2022]
Abstract
Hirschsprung's disease (HSCR) is a developmental disorder of the enteric nervous system, which occurs due to the failure of neural crest cells to fully colonize the gut during embryonic development. It is characterized by the absence of the enteric ganglia in a variable length of the intestine. Substantial progress has been made in understanding the genetic basis of HSCR with the help of advanced genetic analysis techniques and animal models. More than 11 genes have been found to be involved in the pathogenesis of HSCR. The RET gene is the most important susceptibility gene involved in HSCR with both coding and non- coding sequence mutations. Due to phenotypic diversity and genetic complexity observed in HSCR, mutational analysis has limited practical value in genetic counseling and clinical practice. In this review, we discuss the progress that has been made in understanding the molecular genetics of HSCR and summarize the currently identified genes as well as interactions between pathways and gene-modifying loci in HSCR.
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Affiliation(s)
- Zhi-Wen Pan
- Institute of Cell Biology, Zhejiang University Medical School, 388 Yuhangtang Road, Hangzhou 310058, People's Republic of China
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Hirschsprung's disease and variants in genes that regulate enteric neural crest cell proliferation, migration and differentiation. J Hum Genet 2012; 57:485-93. [PMID: 22648184 DOI: 10.1038/jhg.2012.54] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Hirschsprung's disease (HSCR) results from failed colonization of the embryonic gut by enteric neural crest cells (ENCCs); colonization requires RET proto-oncogene (RET) signaling. We sequenced RET to identify coding and splice-site variants in a population-based case group and we tested for associations between HSCR and common variants in RET and candidate genes (ASCL1, homeobox B5 (HOXB5), L1 cell adhesion molecule (L1CAM), paired-like homeobox 2b (PHOX2B), PROK1 and PROKR1) chosen because they are involved in ENCC proliferation, migration and differentiation in animal models. We conducted a nested case-control study of 304 HSCR cases and 1215 controls. Among 38 (12.5%) cases with 34 RET coding and splice-site variants, 18 variants were previously unreported. We confirmed associations with common variants in HOXB5 and PHOX2B but the associations with variants in ASCL1, L1CAM and PROK1 were not significant after multiple comparisons adjustment. RET variants were strongly associated with HSCR (P-values between 10(-3) and 10(-31)) but this differed by race/ethnicity: associations were absent in African-Americans. Our population-based study not only identified novel RET variants in HSCR cases, it showed that common RET variants may not contribute to HSCR in all race/ethnic groups. The findings for HOXB5 and PHOX2B provide supportive evidence that genes regulating ENCC proliferation, migration and differentiation could be risk factors for HSCR.
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Abstract
The pathogenesis of diverticular disease is still poorly understood and considered to be multifactorial. Whereas classical pathogenetic concepts have focused on risk factors including increasing age, low-fiber diet and connective tissue disorders, novel concepts take into account that patients with diverticular disease exhibit disturbed intestinal motility patterns (that may result in functional obstruction and painful sensations) therefore postulating an underlying enteric neuro-/myopathy. Recent studies including quantitative evaluations of the enteric nervous system (ENS) in diverticular disease yielded hypoganglionic conditions of both myenteric and submucosal plexus as well as a nerve tissue remodeling in chronic diverticular disease. The disturbed neuromuscular communication was proven by demonstrating alterations in several enteric neurotransmitter systems, exemplified for the cholinergic, serotonergic, nitrergic system as well as for vasointestinal peptide, galanin and tachykinins. Novel lines of evidence have added the involvement of neurotrophic factors such as glial cell line-derived neurotrophic factor which is supposed to regulate ENS development and maintenance and which is downregulated in patients with diverticular disease. Consistent with the hypothesis of an enteric myopathy, deficits in smooth muscle integrity and composition such as hypertrophy, fibrotic transformation and gene expression deficits could be delineated. Taken together, the structural and functional findings on alterations of the ENS and the enteric musculature in diverticular disease provide evidence to strengthen the hypothesis that an enteric neuro-/myopathy may contribute to the development of colonic diverticula and the generation of symptoms in the course of the disease.
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Affiliation(s)
- Martina Böttner
- Department of Anatomy, Christian-Albrechts University of Kiel, Kiel, Germany.
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Male and female differential reproductive rate could explain parental transmission asymmetry of mutation origin in Hirschsprung disease. Eur J Hum Genet 2012; 20:917-20. [PMID: 22395866 DOI: 10.1038/ejhg.2012.35] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
Hirschsprung disease (HSCR, aganglionic megacolon) is a complex and heterogeneous disease with an incidence of 1 in 5000 live births. Despite the multifactorial determination of HSCR in the vast majority of cases, there is a monogenic subgroup for which private rare RET coding sequence mutations with high penetrance are found (45% of HSCR familial cases). An asymmetrical parental origin is observed for RET coding sequence mutations with a higher maternal inheritance. A parent-of-origin effect is usually assumed. Here we show that a differential reproductive rate for males and females also leads to an asymmetrical parental origin, which was never considered as a possible explanation till now. In the case of HSCR, we show a positive association between penetrance of the mutation and parental transmission asymmetry: no parental transmission asymmetry is observed in sporadic RET CDS mutation carrier cases for which penetrance of the mutation is low, whereas a parental transmission asymmetry is observed in affected sib-pairs for which penetrance of the mutation is higher. This allows us to conclude that the explanation for this parental asymmetry is that more severe mutations have resulted in a differential reproductive rate between male and female carriers.
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Hirschsprung's disease and medullary thyroid carcinoma: 15-year experience with molecular genetic screening of the RET proto-oncogene. Pediatr Surg Int 2012; 28:123-8. [PMID: 21986619 DOI: 10.1007/s00383-011-2993-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
PURPOSE Inactivating germline mutations in the RET proto-oncogene are the major genetic cause of Hirschsprung's disease (HD). In some cases, HD can be associated with medullary thyroid carcinoma (MTC) that is commonly caused by activating RET mutations. METHODS The retrospective and prospective genetic analyses of 157 patients with HD operated on between December 1979 and June 2011 were carried out. DNA was isolated from peripheral leukocytes. HD patients and family members were tested for RET mutations by direct sequencing and single-strand conformation polymorphism methods. RESULTS RET mutations were detected in 16 patients (10%). Association with MTC was found in two families, other eight families had a mutation with potentially high risk of MTC development and four novel mutations were detected. Total colonic aganglionosis was noted to have a high mutation detection rate (40%). Three patients underwent total thyroidectomy (two had clinical manifestation of MTC, one C-cell hyperplasia). CONCLUSION Results show the benefit of systematic RET mutation screening in HD patients in order to identify the risk of MTC in the preclinical stage of the disease. All patients should be tested for RET mutations at least in exon 10, and now additionally in exon 11 and 13, as well.
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Downregulation of Notch-1/Jagged-2 in human colon tissues from Hirschsprung disease patients. Int J Colorectal Dis 2012; 27:37-41. [PMID: 21892607 DOI: 10.1007/s00384-011-1295-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/03/2011] [Indexed: 02/04/2023]
Abstract
PURPOSE Recent studies have shown that the Notch pathways play important roles in the differentiation and development of neurons. Hirschsprung disease (HSCR) is characterized by the absence of intramural ganglion cells in the nerve plexuses of the distal gut. However, putative Notch function in enteric nervous system (ENS) development and the etiology of HSCR is unknown. MATERIALS AND METHODS The aganglionosis segments of 30 HSCR patients were introduced to investigate the expression pattern of Notch-1 and Jagged-2 using immunohistochemical staining, reverse transcriptase polymerase chain reaction (RT-PCR), and Western blot analysis. RESULTS Intensive Notch-1 and Jagged-2 staining was detected in the submucosal and the myenteric plexuses in normal or oligoganglionosis segments. Aganglionosis segments from HSCR patients contained no plexuses and thus not labeled with Notch-1 and Jagged-2. Western blot analysis revealed reduced Notch-1 and Jagged-2 protein levels, and RT-PCR revealed reduced Notch-1 and Jagged-2 mRNA in the aganglionosis segments of HSCR patients. CONCLUSIONS This study is the first illustration of Notch-1 and Jagged-2 expression in human tissues from non-cancerous disease and sets up the base for further investigations of Notch function in ENS development and intestinal motility.
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Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, Wain KE, Williams ES, Aradhya S, Kearney HM, Ledbetter DH, South ST, Thorland EC, Martin CL. Towards an evidence-based process for the clinical interpretation of copy number variation. Clin Genet 2011; 81:403-12. [PMID: 22097934 DOI: 10.1111/j.1399-0004.2011.01818.x] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The evidence-based review (EBR) process has been widely used to develop standards for medical decision-making and to explore complex clinical questions. This approach can be applied to genetic tests, such as chromosomal microarrays, in order to assist in the clinical interpretation of certain copy number variants (CNVs), particularly those that are rare, and guide array design for optimal clinical utility. To address these issues, the International Standards for Cytogenomic Arrays Consortium has established an EBR Work Group charged with building a framework to systematically assess the potential clinical relevance of CNVs throughout the genome. This group has developed a rating system enumerating the evidence supporting or refuting dosage sensitivity for individual genes and regions that considers the following criteria: number of causative mutations reported; patterns of inheritance; consistency of phenotype; evidence from large-scale case-control studies; mutational mechanisms; data from public genome variation databases; and expert consensus opinion. The system is designed to be dynamic in nature, with regions being reevaluated periodically to incorporate emerging evidence. The evidence collected will be displayed within a publically available database, and can be used in part to inform clinical laboratory CNV interpretations as well as to guide array design.
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Affiliation(s)
- E R Riggs
- Department of Human Genetics, Emory University School of Medicine, Atlanta, GA 30322, USA
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So MT, Leon TYY, Cheng G, Tang CSM, Miao XP, Cornes BK, Ngo DN, Cui L, Ngan ESW, Lui VCH, Wu XZ, Wang B, Wang H, Yuan ZW, Huang LM, Li L, Xia H, Zhu D, Liu J, Nguyen TL, Chan IHY, Chung PHY, Liu XL, Zhang R, Wong KKY, Sham PC, Cherny SS, Tam PKH, Garcia-Barcelo MM. RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. PLoS One 2011; 6:e28986. [PMID: 22174939 PMCID: PMC3235168 DOI: 10.1371/journal.pone.0028986] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Accepted: 11/17/2011] [Indexed: 12/21/2022] Open
Abstract
Rare (RVs) and common variants of the RET gene contribute to Hirschsprung disease (HSCR; congenital aganglionosis). While RET common variants are strongly associated with the commonest manifestation of the disease (males; short-segment aganglionosis; sporadic), rare coding sequence (CDS) variants are more frequently found in the lesser common and more severe forms of the disease (females; long/total colonic aganglionosis; familial). Here we present the screening for RVs in the RET CDS and intron/exon boundaries of 601 Chinese HSCR patients, the largest number of patients ever reported. We identified 61 different heterozygous RVs (50 novel) distributed among 100 patients (16.64%). Those include 14 silent, 29 missense, 5 nonsense, 4 frame-shifts, and one in-frame amino-acid deletion in the CDS, two splice-site deletions, 4 nucleotide substitutions and a 22-bp deletion in the intron/exon boundaries and 1 single-nucleotide substitution in the 5′ untranslated region. Exonic variants were mainly clustered in RET the extracellular domain. RET RVs were more frequent among patients with the most severe phenotype (24% vs. 15% in short-HSCR). Phasing RVs with the RET HSCR-associated haplotype suggests that RVs do not underlie the undisputable association of RET common variants with HSCR. None of the variants were found in 250 Chinese controls.
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Affiliation(s)
- Man-Ting So
- Department of Surgery, University of Hong Kong, Hong Kong, China
| | | | - Guo Cheng
- Department of Surgery, University of Hong Kong, Hong Kong, China
| | | | - Xiao-Ping Miao
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | | | - Diem Ngoc Ngo
- Department of Human Genetics, National Hospital of Pediatrics, Hanoi, Vietnam
| | - Long Cui
- Department of Surgery, University of Hong Kong, Hong Kong, China
| | - Elly Sau-Wai Ngan
- Department of Surgery, University of Hong Kong, Hong Kong, China
- Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, China
| | - Vincent Chai-Hang Lui
- Department of Surgery, University of Hong Kong, Hong Kong, China
- Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, China
| | - Xuan-Zhao Wu
- Department of Surgery, Guiyang Medical College Affiliated Hospital, Guiyang, China
| | - Bin Wang
- Shenzhen Children's Hospital, Shenzhen, China
| | | | - Zheng-Wei Yuan
- Shengjing Hospital, China Medical University, Shenyang, China
| | | | - Long Li
- Capital Institute of Pediatrics, Beijing, China
| | - Huimin Xia
- Guangzhou Women and Children's Medical Centre, Guangzhou, China
| | - Deli Zhu
- Guangzhou Women and Children's Medical Centre, Guangzhou, China
| | - Juncheng Liu
- Department of Pediatric Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Thanh Liem Nguyen
- Department of Human Genetics, National Hospital of Pediatrics, Hanoi, Vietnam
| | - Ivy Hau-Yee Chan
- Department of Surgery, University of Hong Kong, Hong Kong, China
| | | | - Xue-Lai Liu
- Department of Surgery, University of Hong Kong, Hong Kong, China
| | - Ruizhong Zhang
- Department of Surgery, University of Hong Kong, Hong Kong, China
| | | | - Pak-Chung Sham
- Department of Psychiatry, University of Hong Kong, Hong Kong, China
- Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, China
- Genome Research Centre of the University of Hong Kong, Hong Kong, China
| | - Stacey S. Cherny
- Department of Psychiatry, University of Hong Kong, Hong Kong, China
| | - Paul Kwong-Hang Tam
- Department of Surgery, University of Hong Kong, Hong Kong, China
- Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, China
| | - Maria-Mercè Garcia-Barcelo
- Department of Surgery, University of Hong Kong, Hong Kong, China
- Centre for Reproduction, Development and Growth, University of Hong Kong, Hong Kong, China
- * E-mail:
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Wallace AS, Anderson RB. Genetic interactions and modifier genes in Hirschsprung's disease. World J Gastroenterol 2011; 17:4937-44. [PMID: 22174542 PMCID: PMC3236992 DOI: 10.3748/wjg.v17.i45.4937] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2011] [Revised: 06/09/2011] [Accepted: 06/16/2011] [Indexed: 02/06/2023] Open
Abstract
Hirschsprung’s disease is a congenital disorder that occurs in 1:5000 live births. It is characterised by an absence of enteric neurons along a variable region of the gastrointestinal tract. Hirschsprung’s disease is classified as a multigenic disorder, because the same phenotype is associated with mutations in multiple distinct genes. Furthermore, the genetics of Hirschsprung’s disease are highly complex and not strictly Mendelian. The phenotypic variability and incomplete penetrance observed in Hirschsprung’s disease also suggests the involvement of modifier genes. Here, we summarise the current knowledge of the genetics underlying Hirschsprung’s disease based on human and animal studies, focusing on the principal causative genes, their interactions, and the role of modifier genes.
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Burlet P, Steichen C, Hesters L, Gigarel N, Kerbrat V, Frydman R, Munnich A, Amiel J, Frydman N, Steffann J. Successful pre-implantation genetic diagnosis for Hirschsprung disease. Clin Genet 2011; 80:403-5. [PMID: 23464651 DOI: 10.1111/j.1399-0004.2011.01634.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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