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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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Jabeen R, Babar ME, Ahmad J, Awan AR. Novel mutations of endothelin-B receptor gene in Pakistani patients with Waardenburg syndrome. Mol Biol Rep 2011; 39:785-8. [PMID: 21547364 DOI: 10.1007/s11033-011-0799-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2010] [Accepted: 04/29/2011] [Indexed: 01/30/2023]
Abstract
Mutations in EDNRB gene have been reported to cause Waardenburg-Shah syndrome (WS4) in humans. We investigated 17 patients with WS4 for identification of mutations in EDNRB gene using PCR and direct sequencing technique. Four genomic mutations were detected in four patients; a G to C transversion in codon 335 (S335C) in exon 5 and a transition of T to C in codon (S361L) in exon 5, a transition of A to G in codon 277 (L277L) in exon 4, a non coding transversion of T to A at -30 nucleotide position of exon 5. None of these mutations were found in controls. One of the patients harbored two novel mutations (S335C, S361L) in exon 5 and one in Intronic region (-30exon5 A>G). All of the mutations were homozygous and novel except the mutation observed in exon 4. In this study, we have identified 3 novel mutations in EDNRB gene associated with WS4 in Pakistani patients.
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Affiliation(s)
- Raheela Jabeen
- Institute of Biochemistry & Biotechnology, University of Veterinary and Animal Sciences, Outfall Road, CivilLines, Lahore, Pakistan
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Wu TT, Tsai TW, Chang H, Su CC, Li SY, Lai HS, Li C. Polymorphisms of the RET gene in hirschsprung disease, anorectal malformation and intestinal pseudo-obstruction in Taiwan. J Formos Med Assoc 2010; 109:32-8. [PMID: 20123584 DOI: 10.1016/s0929-6646(10)60019-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND/PURPOSE Mutations in the receptor tyrosine kinase RET gene are associated with Hirschsprung disease (HD), which is also known as congenital intestinal aganglionosis. We found an association with specific alleles in five single nucleotide polymorphism (SNP) sites of the RET gene in our HD patients. METHODS We compared the association of specific RET SNP alleles in patients with severe GI disorders such as anorectal malformation (ARM) or pediatric intestinal pseudo-obstruction (IPO) to that in HD patients. Sixty-four HD, 23 ARM and 35 IPO patients were included. Genomic DNA extracted from blood samples was analyzed by polymerase chain reaction and DNA sequencing analysis. RESULTS The allele distributions of all five RET SNPs in the HD patients deviated from those in the normal population (p < 0.05), whereas those of the ARM patients did not. The allele distributions of these RET SNPs in the IPO patients were all significantly different from those in the HD patients. Allele distributions of exon 2 and 13 in the IPO patients were also significantly different from those of the normal population. The frequencies of all the HD-predominant alleles were lower in the HD patients than the normal population, and were even lower in the IPO patients. CONCLUSION This study strengthens the association of specific RET SNP alleles with typical HD in Taiwan.
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Affiliation(s)
- Trang-Tiau Wu
- Department of Pediatric Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan
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Abstract
PURPOSE Hirschsprung disease is characterized by the absence of intramural ganglion cells in the myenteric and submucosal plexuses within distal intestine, because of a fail in the enteric nervous system formations process. Endothelin-3-endothelin receptor B signaling pathway is known to play an essential role in this process. The aim of this study was to evaluate the implication of the EDN3 and EDNRB genes in a series of patients with Hirschsprung disease from Spain and determinate their mutational spectrum. METHODS We performed the mutational screening of both genes in 196 patients with Hirschsprung disease using denaturing high-performance liquid chromatography technology. A case-control study using TaqMan Technology was also carried out to evaluate some common polymorphisms and haplotypes as susceptibility factors for Hirschsprung disease. RESULTS Besides several novel mutations in both genes, we found a truncating mutation in an alternative isoform of EDNRB. Interestingly, we obtained an overrepresentation of a specific EDN3 haplotype in cases versus controls. CONCLUSIONS Our results suggest that the isoform EDNRB Delta 3 might be playing an essential role in the formation of enteric nervous system. In addition, based on the haplotype distribution, EDN3 might be considered as a common susceptibility gene for sporadic Hirschsprung disease in a low-penetrance fashion.
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Abstract
Hirschsprung's disease (HSCR) is a developmental disorder characterized by the absence of ganglion cells in the lower digestive tract. Aganglionosis is attributed to a disorder of the enteric nervous system (ENS) whereby ganglion cells fail to innervate the lower gastrointestinal tract during embryonic development. HSCR is a complex disease that results from the interaction of several genes and manifests with low, sex-dependent penetrance and variability in the length of the aganglionic segment. The genetic complexity observed in HSCR can be conceptually understood in light of the molecular and cellular events that take place during the ENS development. DNA alterations in any of the genes involved in the ENS development may interfere with the colonization process, and represent a primary etiology for HSCR. This review will focus on the genes known to be involved in HSCR pathology, how they interact, and on how technology advances are being employed to uncover the pathological processes underlying this disease.
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Chin TW, Chiu CY, Tsai HL, Liu CS, Wei CF, Jap TS. Analysis of the RET gene in subjects with sporadic Hirschsprung's disease. J Chin Med Assoc 2008; 71:406-10. [PMID: 18772120 DOI: 10.1016/s1726-4901(08)70091-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND Hirschsprung's disease (HSCR), or aganglionic megacolon, is a hereditable disease of the enteric nervous system. It is an embryonic developmental disorder characterized by the absence of ganglion cells in the lower enteric plexus. Gut motility is compromised in HSCR, with consequent risk of intestinal obstruction. METHODS We sequenced the RET gene and characterized the clinical manifestations in 15 unrelated Chinese patients (9 males, 6 females; age range, 2-21 years) with sporadic HSCR. Genomic DNA extraction, PCR and DNA sequence analysis were performed according to standard procedures. RESULTS We identified heterozygous RET gene mutations in 2 patients. The mutations included a missense mutation in exon 2 (CGC --> CAC) resulting in a substitution of arginine by histidine at codon 67 (patient 1), and a missense mutation in exon 3 (TAC --> AAC) resulting in a substitution of tyrosine by asparagine at codon 146 (patient 2). The pathological findings disclosed short-segment HSCR in patient 1 and long-segment HSCR in patient 2, respectively. CONCLUSION We identified RET gene mutations in 2 of 15 patients with HSCR in Taiwan. The Y146N mutation we identified was novel.
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Affiliation(s)
- Tai-Wai Chin
- Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China
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Abstract
BACKGROUND Endothelin-B receptor (EDNRB) signaling pathway is associated for Hirschsprung disease (HSCR). The aim of this study was to investigate the EDNRB gene mutation in patients with HSCR in Taiwan and correlate the genotype and phenotype. PATIENTS AND METHODS Using polymerase chain reaction amplification and direct sequencing, we screened for mutations in the coding regions and intron/exon boundaries of the EDNRB gene in 39 isolated HSCR cases and compared them with those in 400 control chromosomes. RESULTS In 3 cases, heterozygous variations in exon 1 and 2 of the EDNRB gene predicted missense mutations of the first cytosolic (M132I), second transmembrane (I157V), second exoplasmic (M173T), and third transmembrane (V185M) domains of the EDNRB protein. Three of the 4 mutations in our study have not been reported previously. For total 39 unrelated cases, the mutation rates were estimated to be 10% (3 of 30) for short-segment HSCR and 7.7% (3 of 39) for all HSCR cases. CONCLUSIONS We did not detect a significant genotype-phenotype correlation. In conclusion, this study identified 4 mutations within the EDNRB gene associated with HSCR. Because HSCR is a multifactorial and multigene disorder, the higher mutation rate of 10% for short-segment HSCR suggests the important role that the EDNRB gene plays in the pathogenesis of short-segment HSCR in Taiwan.
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Ghoul A, Serova M, Le Tourneau C, Aïssat N, Hammel P, Raymond E, Faivre S. Role of the endothelins and endothelin receptors in cancer cell signaling and angiogenesis. Target Oncol 2007. [DOI: 10.1007/s11523-007-0056-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Kim JH, Yoon KO, Kim H, Kim JK, Kim JW, Lee SK, Seo JM. New variations of the EDNRB gene and its association with sporadic Hirschsprung's disease in Korea. J Pediatr Surg 2006; 41:1708-12. [PMID: 17011274 DOI: 10.1016/j.jpedsurg.2006.05.042] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND/PURPOSE The endothelin receptor B (EDNRB) signaling pathway, which is the second major susceptible gene for Hirschsprung's disease (HSCR), is crucial for the development of the enteric nervous system. The allele frequency of polymorphisms was mostly tested in the American and European population, but the data of an ethnically diverse, non-Caucasian population are unclear. To further investigate the variants and haplotypes of the EDNRB gene, this study examined sequence variations in Korean patients with sporadic HSCR. METHODS All 8 exons and intron/exon boundaries of the EDNRB gene in 18 Korean patients with sporadic HSCR and 84 healthy individuals were screened using PCR amplification and direct sequencing. RESULTS A total of 8 different nucleotide substitutions were identified. Of these, 4 were new variants (promoter-116C>T; 5'UTR-121G>T; IVS4+62C>A; IVS5+121G>C) and the others were previously described variants. The distribution of variations was even different from that reported for Chinese and Japanese subjects as well as other ethnic groups. This study also analyzed the haplotypes for an association between the variants identified with HSCR. CONCLUSIONS This study identified additional sequence variants of the EDNRB gene, but the estimated EDNRB haplotypes did not show any disease risk.
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Affiliation(s)
- Jeong-Hyun Kim
- School of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
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Sangkhathat S, Kusafuka T, Chengkriwate P, Patrapinyokul S, Sangthong B, Fukuzawa M. Mutations and polymorphisms of Hirschsprung disease candidate genes in Thai patients. J Hum Genet 2006; 51:1126-1132. [PMID: 17009072 DOI: 10.1007/s10038-006-0064-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2006] [Accepted: 08/28/2006] [Indexed: 01/24/2023]
Abstract
Mutation and polymorphism data for Hirschsprung disease (HSCR) varies among ethnic groups. Single nucleotide polymorphisms (SNP) of RET proto-oncogene (RET) were recently shown to be associated with the disease, and with disease severity, in different populations. In this study, comprehensive analysis of RET, GDNF, EDNRB, ET-3, and SOX-10 genes among sporadic HSCR in Thailand was conducted by standard PCR-SSCP, RFLP, and sequencing methods. Of 41 patients, 30 cases had rectosigmoid disease (RSD) and 11 cases were assigned to the long-segment disease (LSD) group. Four missense mutations of RET, S100M, R231H, T278N, and G533S, were identified in three patients. One novel missense mutation, V111Q, was detected in EDNRB. For ET-3, two novel missense mutations, D166E and C173R, occurred concomitantly in a patient. The incidence of missense mutation was significantly higher in our female HSCR patient than in the male counterpart. Statistical analysis of the SNPs revealed a significant difference between allele distribution of RET L769L in patients in the LSD and RSD groups. The predominant genotype construct of RET A45A/L769L in our HSCR was GG/GG, which is obviously different from results from all previous studies. The GG/GG genotype construct was associated with RSD and with males. The study also detected a variant allele of RET S836S which has never been reported in Asian cohorts.
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Affiliation(s)
- Surasak Sangkhathat
- Pediatric Surgery Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hadyai, Songkhla, 90110, Thailand.
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takeshi Kusafuka
- Division of Pediatric Surgery, Department of Surgery, Nihon University School of Medicine, 30-1 Oyaguchikami-machi, Itabashi-ku, Tokyo, 173-8610, Japan
| | - Piyawan Chengkriwate
- Pediatric Surgery Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hadyai, Songkhla, 90110, Thailand
| | - Sakda Patrapinyokul
- Pediatric Surgery Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hadyai, Songkhla, 90110, Thailand
| | - Burapat Sangthong
- Pediatric Surgery Unit, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hadyai, Songkhla, 90110, Thailand
| | - Masahiro Fukuzawa
- Department of Pediatric Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
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Lantieri F, Griseri P, Puppo F, Campus R, Martucciello G, Ravazzolo R, Devoto M, Ceccherini I. Haplotypes of the human RET proto-oncogene associated with Hirschsprung disease in the Italian population derive from a single ancestral combination of alleles. Ann Hum Genet 2006; 70:12-26. [PMID: 16441254 DOI: 10.1111/j.1529-8817.2005.00196.x] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
The RET proto-oncogene is the major gene involved in the complex genetics of Hirschsprung disease (HSCR), or aganglionic megacolon, showing causative loss-of-function mutations in 15-30% of the sporadic cases. Several RET polymorphisms and haplotypes have been described in association with the disease, suggesting a role for this gene in HSCR predisposition, also in the absence of mutations in the coding region. Finally, the presence of a functional variant in intron 1 has repeatedly been proposed to explain such findings. Here we report a case-control study conducted on 97 Italian HSCR sporadic patients and 85 population matched controls, using 13 RET polymorphisms distributed throughout the gene, from the basal promoter to the 3'UTR. Linkage disequilibrium and haplotype analyses have shown increased recombination between the 5' and 3' portions of the gene and an over-representation, in the cases studied, of two haplotypes sharing a common allelic combination that extends from the promoter up to intron 5. We propose that these two disease-associated haplotypes derive from a single founding locus, extending up to intron 19 and successively rearranged in correspondence with a high recombination rate region located between the proximal and distal portions of the gene. Our results suggests the possibility that a common HSCR predisposing variant, in linkage disequilibrium with such haplotypes, is located further downstream than the previously suggested interval encompassing intron 1.
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Affiliation(s)
- F Lantieri
- Laboratorio di Genetica Molecolare, Istituto Giannina Gaslini, Genova, Italy, 16148
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Kim JH, Yoon KO, Kim JK, Kim JW, Lee SK, Kong SY, Seo JM. Novel mutations of RET gene in Korean patients with sporadic Hirschsprung's disease. J Pediatr Surg 2006; 41:1250-4. [PMID: 16818057 DOI: 10.1016/j.jpedsurg.2006.03.051] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND/PURPOSE Hirschsprung's disease (HSCR) is a congenital abnormality that can cause an intestinal obstruction. Although HSCR demonstrates a sex-modified polygenic inheritance with contributions from multiple genes, mutations in the RET gene are believed to be the major sign of susceptibility in the development of disease. The allele frequency of polymorphisms was mostly tested in the American and European population, but the data of an ethnically diverse nonwhite population are unclear. METHODS All 21 exons and intron/exon boundaries of the RET gene in 18 Korean patients with sporadic HSCR and 84 normal individuals were screened using polymerase chain reaction amplification and direct sequencing. RESULTS A total of 11 different nucleotide substitutions were identified. Of these, 2 were new missense mutations (C558Y, cysteine-rich domain; R844W, tyrosine kinase domain) and 9 previously described variants. This study also analyzed the haplotypes for the association between the variants identified with HSCR, but the estimated RET haplotypes did not show any disease risk. CONCLUSIONS This study identified additional mutations of RET gene, which represents the first comprehensive genetic dissection of sporadic HSCR disease in Koreans.
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Affiliation(s)
- Jeong-Hyun Kim
- School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, South Korea
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Chen WC, Chang SS, Sy ED, Tsai MC. A De Novo Novel Mutation of the EDNRB Gene in a Taiwanese Boy with Hirschsprung Disease. J Formos Med Assoc 2006; 105:349-54. [PMID: 16618617 DOI: 10.1016/s0929-6646(09)60128-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. Although mutations in eight different genes (EDNRB, EDN3, ECE1, SOX10, RET, GDNF, NTN, SIP1) have been identified in affected individuals, it is now clear that RET and EDNRB are the primary genes implicated in the etiology of HSCR. All eight genes are involved in the early development of the enteric nervous system, and most act through two distinct biochemical pathways mediated by RET and EDNRB. Mutations in RET and EDNRB account for up to 50% and 5% of HSCR cases in the general population, respectively. Interaction between these two signaling pathways could modify RET expression and, therefore, HSCR phenotype. Here, we report the case of a 1-year-old Taiwanese boy who presented with abdominal distension since birth and bilious vomiting after feeding. HSCR (short-segment type) was diagnosed based on X-ray, lower gastrointestinal series and biopsy findings. Mutation analysis revealed a heterozygous T>C missense mutation in exon 1 of the EDNRB gene, that substitutes the highly conserved cysteine-90 residue in the extracellular domain of the G protein-coupled receptor with an arginine residue (C90R). No RET gene mutation was detected in this patient.
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Affiliation(s)
- Wen-Chau Chen
- Department of Emergency Medicine, National Cheng Kung University Medical College and Hospital, Tainan, Taiwan
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Soufir N, Meziani R, Lacapère JJ, Bertrand G, Fumeron F, Bourillon A, Gérard B, Descamps V, Crickx B, Ollivaud L, Archimbaud A, Lebbe C, Basset-Seguin N, Saiag P, Grandchamp B. Association Between Endothelin Receptor B Nonsynonymous Variants and Melanoma Risk. ACTA ACUST UNITED AC 2005; 97:1297-301. [PMID: 16145050 DOI: 10.1093/jnci/dji253] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The endothelin signaling pathway plays a crucial role in melanocyte differentiation and migration. In this study, we investigated whether germline mutations of endothelin receptor B (EDNRB), a gene involved in Hirschsprung disease (HSCR), could also predispose for malignant melanoma (MM). The coding region of EDNRB was sequenced in 137 MM patients and in 130 ethnically matched Caucasian control subjects. Six nonsynonymous EDNRB variants were found in 15 patients (11%), but only two were found in four control subjects (3%, odds ratio [OR] = 3.87, 95% confidence interval [CI] = 1.25 to 12; P = .012). Overall, 14 out of 15 MM patients carried EDNRB mutations reported in HSCR, some of which had previously been shown to lead to loss of function. In multivariable logistic regression analysis including skin type, eye and hair color, number of nevi, and dorsal lentigines (freckles), the association between EDNRB mutations and MM risk remained statistically significant (OR = 19.9, 95% CI = 1.34 to 296.2; P = .03). Our data strongly suggest that EDNRB is involved in predisposition for two different multigenic disorders, HSCR and melanoma.
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Affiliation(s)
- Nadem Soufir
- Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, AP-HP, Faculté de Médecine, Paris VII, Paris, France.
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Wu TT, Tsai TW, Chu CT, Lee ZF, Hung CM, Su CC, Li SY, Hsieh M, Li C. Low RET mutation frequency and polymorphism analysis of the RET and EDNRB genes in patients with Hirschsprung disease in Taiwan. J Hum Genet 2005; 50:168-174. [PMID: 15834508 DOI: 10.1007/s10038-005-0236-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2004] [Accepted: 01/20/2005] [Indexed: 01/17/2023]
Abstract
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder characterized by the absence of ganglion cells in the nerve plexuses of the lower digestive tract, resulting in intestinal obstruction in neonates. Mutations in genes of the RET receptor tyrosine kinase and endothelin receptor B (EDNRB) signaling pathways have been shown to be associated in HSCR patients. In this study, we collected genomic DNA samples from 55 HSCR patients in central Taiwan and analyzed the coding regions of the RET and EDNRB genes by PCR amplification and DNA sequencing. In the 55 patients, an A to G transition was detected in two (identical twin brothers). The mutation was at the end of RET exon 19 at codon 1062 (Y1062C), a reported critical site for the signaling pathways. Single nucleotide polymorphisms (SNP) in exons 2, 7, 11, 13, and 15 of RET and exon 4 of EDNRB in the HSCR patients or controls were detected. The differences between patients and controls in allele distribution of the five RET polymorphic sites were statistically significant. The most frequent genotype encompassing exons 2 and 13 SNPs (the polymorphic sites with the highest percentage of heterozygotes) was AA/GG in patients, which was different from the AG/GT in the normal controls. Transmission disequilibrium was observed in exons 2, 7, and 13, indicating nonrandom association of the susceptibility alleles with the disease in the patients. This study represents the first comprehensive genetic analysis of HSCR disease in Taiwan.
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Affiliation(s)
- Trang-Tiau Wu
- Department of Pediatric Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan, Republic of China
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan, Republic of China
| | - Tsui-Wei Tsai
- Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China
| | - Chao-Ta Chu
- Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China
| | - Zen-Fung Lee
- Division of Pediatric Surgery, God's Heart Hospital, Chiayi, Taiwan, Republic of China
| | - Chuan-Mao Hung
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan, Republic of China
- Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China
| | - Ching-Chyuan Su
- Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan, Republic of China
- Tian-Sheng Memorial Hospital, Tong Kang, Pin-Tong, Taiwan, Republic of China
| | - Shuan-Yow Li
- Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China
| | - Mingli Hsieh
- Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China
- Department of Biology, Tunghai University, Taichung, Taiwan, Republic of China
| | - Chuan Li
- Department of Life Sciences, Chung Shan Medical University, 110 Sec. 1, Chein-Kuo North Road, Taichung, Taiwan, Republic of China.
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Guan T, Li JC, Li MJ, Tou JF. Polymerase chain reaction-single strand conformational polymorphism analysis of rearranged during transfection proto-oncogene in Chinese familial hirschsprung’s disease. World J Gastroenterol 2005; 11:275-9. [PMID: 15633231 PMCID: PMC4205417 DOI: 10.3748/wjg.v11.i2.275] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between mutations of rearranged during transfection (RET) proto-oncogene and Chinese patients with Hirschsprung’s disease (HD), and to elucidate the genetic mechanism of familial HD patient at the molecular level.
METHODS: Genomic DNA was extracted from venous blood of probands and their relatives in two genealogies. Polymerase chain reaction (PCR) products, which were amplified using specific primers (RET, exons 11, 13, 15 and 17), were electrophoresed to analyze the single-strand conformational polymorphism (SSCP) patterns. The positive amplified products were sequenced. Forty-eight sporadic HD patients and 30 normal children were screened for mutations of RET proto-oncogene simultaneously.
RESULTS: Three cases with HD in one family were found to have a G heterozygous insertion at nucleotide 18974 in exon 13 of RET cDNA (18974insG), which resulted in a frameshift mutation. In another family, a heterozygosity for T to G transition at nucleotide 18888 in the same exon which resulted in a synonymous mutation of Leu at codon 745 was detected in the proband and his father. Eight RET mutations were confirmed in 48 sporadic HD patients.
CONCLUSION: Mutations of RET proto-oncogene may play an important role in the pathogenesis of Chinese patients with HD. Detection of mutated RET proto-oncogene carriers may be used for genetic counseling of potential risk for HD in the affected families.
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Affiliation(s)
- Tao Guan
- Department of Lymphology, Institute of Cell Biology, Zhejiang University Medical College, Hangzhou 310031, Zhejiang Province, China
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17
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Affiliation(s)
- Paul K H Tam
- Department of Surgery and Genome Research Centre, The University of Hong Kong, Queen Mary Hospital K15, Pokfulam, Hong Kong, P.R. China.
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Garcia-Barceló M, Sham MH, Lee WS, Lui VCH, Chen BLS, Wong KKY, Wong JSW, Tam PKH. Highly recurrent RET mutations and novel mutations in genes of the receptor tyrosine kinase and endothelin receptor B pathways in Chinese patients with sporadic Hirschsprung disease. Clin Chem 2003; 50:93-100. [PMID: 14633923 DOI: 10.1373/clinchem.2003.022061] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
BACKGROUND Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract. HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system. METHODS Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls. RESULTS We identified 10 novel and 2 previously described mutations in RET, and 4 and 2 novel mutations in EDNRB and in EDN3, respectively. Potential disease-causing mutations were detected in 24% of the patients. The overall mutation rate was 41% in females and 19% in males (P = 0.06). RET mutations occurred in 19% of the patients. R114H in RET was the most prevalent mutation, representing 7% of the patients or 37% of the patients with RET mutations. To date, such a high frequency of a single mutation has never been reported in unrelated HSCR patients. Mutations in EDNRB, EDN3, and GDNF were found in four, two, and none of the patients, respectively. Two patients with mutations in genes of the EDNRB pathway also harbored a mutation in RET. Three novel and three reported polymorphisms were found in EDNRB, EDN3, and GDNF. CONCLUSION This study identifies additional HSCR disease-causing mutations, some peculiar to the Chinese population, and represents the first comprehensive genetic analysis of sporadic HSCR disease in Chinese.
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Affiliation(s)
- Mercè Garcia-Barceló
- Division of Paediatric Surgery, Department of Surgery, University of Hong Kong Medical Center, Queen Mary Hospital, Hong Kong SAR, China
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19
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Abstract
AIM: To investigate the pathogenic mechanism of Hirschsprung’s disease (HD) at the molecular level and to elucidate the relationship between RET oncogene and Chinese patients with HD.
METHODS: Exon 13 of RET oncogene from 20 unrelated HD patients was analyzed with polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP). The positive amplifying products were then sequenced. According to the results of SSCP and DNA sequence, SSCP was done as well for the samples from the family other members of some cases with mutated RET gene.
RESULTS: SSCP analysis indicated that mobility abnormality existed in 4 unrelated HD patients. Direct DNA sequence analysis identified a missense mutation, T to G at the nucleotide 18888 and a frameshift mutation at the nucleotide 18926 insG. In a HD family, the sicked child and his father were the same heterozygous missense mutation (T to G at nucleotide 18888).
CONCLUSION: Among Chinese HD patients, RET gene mutations may exist in considerable proportion with different patterns. These new discoveries indicate that RET mutations may play an important role in the pathogenesis of unrelated HD in the Chinese population. PCR-SSCP combined with DNA sequence can be used as a tool in the genetic diagnosis of HD.
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Affiliation(s)
- Ji-Cheng Li
- Department of Lymphology, Department of Histology and Embryology, Zhejiang University Medical College, Hangzhou 310031, Zhejiang Province, China.
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20
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Kanai M, Numakura C, Sasaki A, Shirahata E, Akaba K, Hashimoto M, Hasegawa H, Shirasawa S, Hayasaka K. Congenital central hypoventilation syndrome: a novel mutation of the RET gene in an isolated case. TOHOKU J EXP MED 2002; 196:241-6. [PMID: 12086152 DOI: 10.1620/tjem.196.241] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Recently, a few genetic abnormalities were identified in congenital central hypoventilation syndrome (CCHS or Ondine's curse). CCHS is often associated with other neurocristopathies, especially with Hirschsprung's disease (HSCR). Mutations of the genes involved in the receptor tyrosine kinase RET (REarranged during Transfection) (RET)-glial cell line-derived neurotrophic factor (GDNF) and/or endothelin 3 (EDN3)-endothelin receptor-B (EDNRB) signaling pathway have been found in some of HSCR patients. In this study, we analyzed candidates for HSCR, namely the RET, GDNF, EDN3 and EDNRB genes in three isolated CCHS patients to confirm the hypothesis that some CCHS patients have a common genetic abnormality with patients having HSCR or other neurocristopathies. We found a novel R114H mutation of the RET gene in one patient. The R114H mutation is unlikely to be a polymorphism and appears to be associated with CCHS. In addition, we also examined the HOX11L2 (RNX) gene, for which knock-out mice showed CCHS-like syndrome in these isolated CCHS patients and did not detected any mutation. Further cases should be analyzed for more candidates to clarify the pathophysiology of CCHS.
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Affiliation(s)
- Masayo Kanai
- Department of Pediatrics, Yamagata University School of Medicine, Japan
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21
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Borghini S, Bocciardi R, Bonardi G, Matera I, Santamaria G, Ravazzolo R, Ceccherini I. Hirschsprung associated GDNF mutations do not prevent RET activation. Eur J Hum Genet 2002; 10:183-7. [PMID: 11973622 DOI: 10.1038/sj.ejhg.5200785] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2001] [Revised: 01/08/2002] [Accepted: 01/16/2002] [Indexed: 11/09/2022] Open
Abstract
Hirschsprung disease (HSCR) is a complex disorder characterised by aganglia of distal gastrointestinal tracts. The highest proportion of both familial and sporadic cases is due to mutations of the RET proto-oncogene. Five germline mutations in the glial cell-line-derived neurotrophic factor (GDNF) gene, one of the RET ligands, have been detected in HSCR patients. Pedigrees analysis and the observed association between these GDNF alterations and RET variants in the same patients raised the question of whether the GDNF gene plays any causative/predisposing role in HSCR pathogenesis. In the present work, we have studied the ability of GDNF proteins, each bearing one of the reported mutations, to activate RET by performing a functional test in cultured neuroblastoma cells. Consistently with the lack of genotype/phenotype correlation in human subjects, our results indicate absence of detectable alterations of mutant GDNF induced RET activation.
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Affiliation(s)
- Silvia Borghini
- Laboratorio di Genetica Molecolare, Istituto G. Gaslini, 16148 Genova, Italy
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22
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Abstract
Hirschsprung disease is the most common congenital malformation of the enteric nervous system. Phenotypic expression is variable because of incomplete penetrance, and the pathogenesis is multifactorial. Although mutations of the RET tyrosine kinase gene remain the most commonly identified cause, there are now eight separate human gene loci identified whose mutations result in this disease. Analysis of these gene products in experimental animal models and cell systems has led to an increasing elucidation of the signaling pathways that are in operation during specific embryonic time stages and that direct the spatial arrangements and differentiation of enteric neuroblasts. Mutation analysis through in vitro cell expression studies has led to detailed descriptions of the affected microdomains of signal pathway receptors and the cellular pathogenesis of abnormal signaling that leads to apoptosis of developing neurons before the completion of enteric nervous system development. The full description of the pathogenesis of this disorder awaits the definition of new genetic loci, multiple gene interactions, and the acknowledgment of random events that may lead to aganglionosis of the distal bowel.
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Affiliation(s)
- William M Belknap
- Section of Pediatric Gastroenterology, Department of Pediatrics, Henry Ford Health System, Detroit, Michigan 48202, USA.
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Abstract
Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a relatively common disorder of neural crest migration. It has a strong genetic basis, although simple Mendelian inheritance is rarely observed. Hirschsprung disease is associated with several other anomalies and syndromes, and animal models for these conditions exist. Mutations in the RET gene are responsible for approximately half of familial cases and a smaller fraction of sporadic cases. Mutations in genes that encode RET ligands (GDNF and NTN); components of another signaling pathway (EDNRB, EDN3, ECE-1); and the transcription factor, SOX10, have been identified in HSCR patients. A subset of these mutations is associated with anomalies of pigmentation and/or hearing loss. For almost every HSCR gene, incomplete penetrance of the HSCR phenotype has been observed, probably due to genetic modifier loci. Thus, HSCR has become a model of a complex polygenic disorder in which the interplay of different genes is currently being elucidated.
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Affiliation(s)
- M A Parisi
- Department of Pediatrics, Children's Hospital and Regional Medical Center, Seattle, Washington, USA
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