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Labat-de-Hoz L, Jiménez MÁ, Correas I, Alonso MA. Regulation of formin INF2 and its alteration in INF2-linked inherited disorders. Cell Mol Life Sci 2024; 81:463. [PMID: 39586895 PMCID: PMC11589041 DOI: 10.1007/s00018-024-05499-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 10/21/2024] [Accepted: 10/31/2024] [Indexed: 11/27/2024]
Abstract
Formins are proteins that catalyze the formation of linear filaments made of actin. INF2, a formin, is crucial for correct vesicular transport, microtubule stability and mitochondrial division. Its activity is regulated by a complex of cyclase-associated protein and lysine-acetylated G-actin (KAc-actin), which helps INF2 adopt an inactive conformation through the association of its N-terminal diaphanous inhibitory domain (DID) with its C-terminal diaphanous autoinhibitory domain. INF2 activation can occur through calmodulin binding, KAc-actin deacetylation, G-actin binding, or association with the Cdc42 GTPase. Mutations in the INF2 DID are linked to focal segmental glomerulosclerosis (FSGS), affecting podocytes, and Charcot-Marie-Tooth disease, which affects Schwann cells and leads to axonal loss. At least 80 pathogenic DID variants of INF2 have been identified, with potential for many more. These mutations disrupt INF2 regulation, leading to excessive actin polymerization. This in turn causes altered intracellular trafficking, abnormal mitochondrial dynamics, and profound transcriptional reprogramming via the MRTF/SRF complex, resulting in mitotic abnormalities and p53-mediated cell death. This sequence of events could be responsible for progressive podocyte loss during glomerular degeneration in FSGS patients. Pharmacological targeting of INF2 or actin polymerization could offer the therapeutic potential to halt the progression of FSGS and improve outcomes for patients with INF2-linked disease.
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Affiliation(s)
- Leticia Labat-de-Hoz
- Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28049, Madrid, Spain
| | - M Ángeles Jiménez
- Instituto de Química Física (IQF) Blas Cabrera, Consejo Superior de Investigaciones Científicas, 28006, Madrid, Spain
| | - Isabel Correas
- Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28049, Madrid, Spain
- Department of Molecular Biology, UAM, 28049, Madrid, Spain
| | - Miguel A Alonso
- Centro de Biología Molecular Severo Ochoa (CBMSO), Consejo Superior de Investigaciones Científicas (CSIC), Universidad Autónoma de Madrid (UAM), 28049, Madrid, Spain.
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2
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Abstract
Almost 25 years have passed since a mutation of a formin gene, DIAPH1, was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of DIAPH1 and six other formin genes (DAAM2, DIAPH2, DIAPH3, FMN2, INF2 and FHOD3) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field.
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Affiliation(s)
| | - Miguel A. Alonso
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain;
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3
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Thakor JM, Parmar G, Mistry KN, Gang S, Rank DN, Joshi CG. Mutational landscape of TRPC6, WT1, LMX1B, APOL1, PTPRO, PMM2, LAMB2 and WT1 genes associated with Steroid resistant nephrotic syndrome. Mol Biol Rep 2021; 48:7193-7201. [PMID: 34546508 DOI: 10.1007/s11033-021-06711-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Accepted: 09/14/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Nephrotic syndrome appears as a group of symptoms like proteinuria, edema and hyperlipidemia. Identification of monogenic forms revealed the physiology and pathogenesis of the SRNS. METHODS AND RESULTS We performed Illumina panel sequencing of seven genes in 90 Indian patients to determine the role of these genetic mutations in nephrotic syndrome prognosis. Samtool was used for variants calling, and SnpEff and Snpsift did variants annotation. Clinical significance and variant classification were performed by the ClinVar database. In SSNS and SRNS patients, we found 0.78% pathogenic and 3.41% likely pathogenic mutations. Pathogenic mutations were found in LAMB2, LMX1B and WT1 genes, while likely pathogenic mutations were found in (6/13) LAMB2, (2/13) LMX1B, (2/13) TRPC6, (2/13) PTPRO and (1/13) PMM2 genes. Approximately 46% likely pathogenic mutations were contributed to the LAMB2 gene in SSNS and SRNS patients. We also detect 30 VUS (variants of uncertain significance), which were found (17/30) pathogenic and (13/30) likely pathogenic by different prediction tools. CONCLUSIONS Multigene panels were used for genetic screening of heterogeneous disorders like nephrotic syndrome in the Indian population. We found pathogenic, likely pathogenic and certain VUS, which were responsible for the pathogenesis of the disease. Therefore, mutational analysis of SSNS and SRNS is necessary to avoid adverse effects of corticosteroids, modify the intensity of immunosuppressing agents, and prevent the disease's progression.
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Affiliation(s)
- Jinal M Thakor
- Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, ADIT Campus, New Vallabh Vidyanagar, 388121, Anand, Gujarat, India
| | - Glory Parmar
- Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, ADIT Campus, New Vallabh Vidyanagar, 388121, Anand, Gujarat, India
| | - Kinnari N Mistry
- Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences, ADIT Campus, New Vallabh Vidyanagar, 388121, Anand, Gujarat, India.
| | - Sishir Gang
- Muljibhai Patel Urological Hospital, Dr. V.V. Desai Road, Nadiad, 387001, Gujarat, India
| | - Dharamshibhai N Rank
- Department of Animal Breeding and Genetics, College of Veterinary Sciences and Animal Husbandry, Anand Agricultural University, Anand, 388110, Gujarat, India
| | - Chaitanya G Joshi
- Department of Animal Biotechnology, College of Veterinary Sciences and Animal Husbandry, Anand Agricultural University, Anand, 388110, Gujarat, India
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Miao J, Pinto E Vairo F, Hogan MC, Erickson SB, El Ters M, Bentall AJ, Kukla A, Greene EL, Hernandez LH, Sethi S, Lazaridis KN, Pichurin PN, Lisi E, Prochnow CA, Zand L, Fervenza FC. Identification of Genetic Causes of Focal Segmental Glomerulosclerosis Increases With Proper Patient Selection. Mayo Clin Proc 2021; 96:2342-2353. [PMID: 34120753 DOI: 10.1016/j.mayocp.2021.01.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 01/25/2021] [Accepted: 01/28/2021] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To increase the likelihood of finding a causative genetic variant in patients with a focal segmental glomerulosclerosis (FSGS) lesion, clinical and histologic characteristics were analyzed. PATIENTS AND METHODS Individuals 18 years and older with an FSGS lesion on kidney biopsy evaluated at Mayo Clinic from November 1, 1999, through October 31, 2019, were divided into 4 groups based on clinical and histologic characteristics: primary FSGS, secondary FSGS with known cause, secondary FSGS without known cause, and undetermined FSGS. A targeted gene panel and a customized gene panel retrieved from exome sequencing were performed. RESULTS The overall rate of detection of a monogenic cause was 42.9% (21/49). Individuals with undetermined FSGS had the highest rate of positivity (87.5%; 7/8) followed by secondary FSGS without an identifiable cause (61.5%; 8/13) and secondary FSGS with known cause (33.3%; 5/15). Four of 5 (80%) individuals in the latter group who had positive genetic testing results also had a family history of kidney disease. Univariate analysis showed that family history of kidney disease (odds ratio [OR], 13.8; 95% CI, 3.7 to 62.4; P<.001), absence of nephrotic syndrome (OR, 8.2; 95% CI, 1.9 to 58.1; P=.004), and female sex (OR, 5.1; 95% CI, 1.5 to 19.9; P=.01) were strong predictors of finding a causative genetic variant in the entire cohort. The most common variants were in the collagen genes (52.4%; 11/21), followed by the podocyte genes (38.1%; 8/21). CONCLUSION In adults with FSGS lesions, proper selection of patients increases the rate of positive genetic testing significantly. The majority of individuals with undetermined FSGS in whom the clinical presentation and histologic parameters are discordant had a genetic diagnosis.
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Affiliation(s)
- Jing Miao
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Filippo Pinto E Vairo
- Department of Clinical Genomics, Mayo Clinic, Rochester, MN; Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | - Marie C Hogan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | | | - Mireille El Ters
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Andrew J Bentall
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Aleksandra Kukla
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | - Eddie L Greene
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN
| | | | - Sanjeev Sethi
- Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN
| | | | | | - Emily Lisi
- Center for Individualized Medicine, Mayo Clinic, Rochester, MN
| | | | - Ladan Zand
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN.
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Labat-de-Hoz L, Alonso MA. The formin INF2 in disease: progress from 10 years of research. Cell Mol Life Sci 2020; 77:4581-4600. [PMID: 32451589 PMCID: PMC11104792 DOI: 10.1007/s00018-020-03550-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Revised: 05/04/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023]
Abstract
Formins are a conserved family of proteins that primarily act to form linear polymers of actin. Despite their importance to the normal functioning of the cytoskeleton, for a long time, the only two formin genes known to be a genetic cause of human disorders were DIAPH1 and DIAPH3, whose mutation causes two distinct forms of hereditary deafness. In the last 10 years, however, the formin INF2 has emerged as an important target of mutations responsible for the appearance of focal segmental glomerulosclerosis, which are histological lesions associated with glomerulus degeneration that often leads to end-stage renal disease. In some rare cases, focal segmental glomerulosclerosis concurs with Charcot-Marie-Tooth disease, which is a degenerative neurological disorder affecting peripheral nerves. All known INF2 gene mutations causing disease map to the exons encoding the amino-terminal domain. In this review, we summarize the structure, biochemical features and functions of INF2, conduct a systematic and comprehensive analysis of the pathogenic INF2 mutations, including a detailed study exon-by-exon of patient cases and mutations, address the impact of the pathogenic mutations on the structure, regulation and known functions of INF2, draw a series of conclusions that could be useful for INF2-related disease diagnosis, and suggest lines of research for future work on the molecular mechanisms by which INF2 causes disease.
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Affiliation(s)
- Leticia Labat-de-Hoz
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain
| | - Miguel A Alonso
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, Spain.
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Trautmann A, Vivarelli M, Samuel S, Gipson D, Sinha A, Schaefer F, Hui NK, Boyer O, Saleem MA, Feltran L, Müller-Deile J, Becker JU, Cano F, Xu H, Lim YN, Smoyer W, Anochie I, Nakanishi K, Hodson E, Haffner D. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 2020; 35:1529-1561. [PMID: 32382828 PMCID: PMC7316686 DOI: 10.1007/s00467-020-04519-1] [Citation(s) in RCA: 193] [Impact Index Per Article: 38.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/07/2020] [Accepted: 02/21/2020] [Indexed: 02/06/2023]
Abstract
Idiopathic nephrotic syndrome newly affects 1-3 per 100,000 children per year. Approximately 85% of cases show complete remission of proteinuria following glucocorticoid treatment. Patients who do not achieve complete remission within 4-6 weeks of glucocorticoid treatment have steroid-resistant nephrotic syndrome (SRNS). In 10-30% of steroid-resistant patients, mutations in podocyte-associated genes can be detected, whereas an undefined circulating factor of immune origin is assumed in the remaining ones. Diagnosis and management of SRNS is a great challenge due to its heterogeneous etiology, frequent lack of remission by further immunosuppressive treatment, and severe complications including the development of end-stage kidney disease and recurrence after renal transplantation. A team of experts including pediatric nephrologists and renal geneticists from the International Pediatric Nephrology Association (IPNA), a renal pathologist, and an adult nephrologist have now developed comprehensive clinical practice recommendations on the diagnosis and management of SRNS in children. The team performed a systematic literature review on 9 clinically relevant PICO (Patient or Population covered, Intervention, Comparator, Outcome) questions, formulated recommendations and formally graded them at a consensus meeting, with input from patient representatives and a dietician acting as external advisors and a voting panel of pediatric nephrologists. Research recommendations are also given.
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Affiliation(s)
- Agnes Trautmann
- Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany
| | - Marina Vivarelli
- Department of Pediatric Subspecialties, Division of Nephrology and Dialysis, Bambino Gesù Pediatric Hospital and Research Center, Rome, Italy
| | - Susan Samuel
- Department of Pediatrics, Section of Pediatric Nephrology, Alberta Children's Hospital, University of Calgary, Calgary, Canada
| | - Debbie Gipson
- Division of Nephrology, University of Michigan, Ann Arbor, MI, USA
| | - Aditi Sinha
- Department of Pediatrics, Division of Nephrology, All India Institute of Medical Sciences, New Delhi, India
| | - Franz Schaefer
- Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, Heidelberg, Germany
| | - Ng Kar Hui
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Olivia Boyer
- Laboratory of Hereditary Kidney Diseases, Imagine Institute, INSERM U1163, Paris Descartes University, Paris, France
- Department of Pediatric Nephrology, Reference Center for Idiopathic Nephrotic Syndrome in Children and Adults, Necker Hospital, APHP, 75015, Paris, France
| | - Moin A Saleem
- Department of Pediatric Nephrology, Bristol Royal Hospital for Children, University of Bristol, Bristol, UK
| | - Luciana Feltran
- Hospital Samaritano and HRim/UNIFESP, Federal University of São Paulo, São Paulo, Brazil
| | | | - Jan Ulrich Becker
- Institute of Pathology, University Hospital of Cologne, Cologne, Germany
| | - Francisco Cano
- Department of Nephrology, Luis Calvo Mackenna Children's Hospital, University of Chile, Santiago, Chile
| | - Hong Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China
| | - Yam Ngo Lim
- Department of Pediatrics, Prince Court Medical Centre, Kuala Lumpur, Malaysia
| | - William Smoyer
- The Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ifeoma Anochie
- Department of Paediatrics, University of Port Harcourt Teaching Hospital, Port Harcourt, Rivers State, Nigeria
| | - Koichi Nakanishi
- Department of Child Health and Welfare (Pediatrics), Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Elisabeth Hodson
- Cochrane Kidney and Transplant, Centre for Kidney Research, The Children's Hospital at Westmead and the Sydney School of Public Health, University of Sydney, Sydney, Australia
| | - Dieter Haffner
- Department of Paediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.
- Department of Paediatric Kidney, Liver and Metabolic Diseases, Paediatric Research Center, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
- Center for Rare Diseases, Hannover Medical School Children's Hospital, Hannover, Germany.
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7
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Rosier M, Guedj M, Calvas P, Julia S, Garnier C, Cambon-Thomsen A, Muñoz Sastre MT. Attitudes of French populations towards the disclosure of unsolicited findings in medical genetics. J Health Psychol 2019; 26:1767-1779. [PMID: 31707852 DOI: 10.1177/1359105319886622] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Next-generation sequencing techniques enable unsolicited findings to be detected. This discovery raises ethical questions concerning the return of these findings. Our study aimed to highlight the views of the general public, patients under supervision and health professionals concerning the acceptability of disclosing unsolicited results to patients. In total, 449 participants assessed scenarios, consisted of all combinations of three factors (patient's information and consent, prevention and treatment of the unsolicited disease and doctor's decision). The response profiles were grouped into six clusters. The participants took ethical aspects into account, but health professionals also considered the medical aspects to a greater extent.
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8
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Guaragna MS, de Brito Lutaif ACG, de Souza ML, Maciel-Guerra AT, Belangero VMS, Guerra-Júnior G, de Mello MP. Promises and pitfalls of whole-exome sequencing exemplified by a nephrotic syndrome family. Mol Genet Genomics 2019; 295:135-142. [PMID: 31520189 DOI: 10.1007/s00438-019-01609-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 09/05/2019] [Indexed: 01/12/2023]
Abstract
High-throughput techniques such as whole-exome sequencing (WES) show promise for the identification of candidate genes that underlie Mendelian diseases such as nephrotic syndrome (NS). These techniques have enabled the identification of a proportion of the approximately 54 genes associated with NS. However, the main pitfall of using WES in clinical and research practice is the identification of multiple variants, which hampers interpretation during downstream analysis. One useful strategy is to evaluate the co-inheritance of rare variants in affected family members. Here, we performed WES of a patient with steroid-resistant NS (SRNS) and intermittent microhematuria. Currently, 15 years after kidney transplantation, this patient presents normal kidney function. The patient was found to be homozygous for a rare MYO1E stop-gain variant, and was heterozygous for rare variants in NS-associated genes, COL4A4, KANK1, LAMB2, ANLN, E2F3, and APOL1. We evaluated the presence or absence of these variants in both parents and 11 siblings, three of whom exhibited a milder phenotype of the kidney disease. Analysis of variant segregation in the family, indicated the MYO1E stop-gain variant as the putative causal variant underlying the kidney disease in the patient and two of her affected sisters. Two secondary variants in COL4A4-identified in some other affected family members-require further functional studies to determine whether they play a role in the development of microhematuria in affected family members. Our data illustrate the difficulties in distinguishing the causal pathogenic variants from incidental findings after WES-based variant analysis, especially in heterogenous genetic conditions, such as NS.
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Affiliation(s)
- Mara Sanches Guaragna
- Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering (CBMEG), State University of Campinas, UNICAMP, Caixa Postal 6010, 13083-875, Campinas, SP, Brazil.
| | - Anna Cristina Gervásio de Brito Lutaif
- Integrated Center of Pediatric Nephrology (CIN), Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas, UNICAMP, Campinas, Brazil
| | - Marcela Lopes de Souza
- Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering (CBMEG), State University of Campinas, UNICAMP, Caixa Postal 6010, 13083-875, Campinas, SP, Brazil
| | | | - Vera Maria Santoro Belangero
- Integrated Center of Pediatric Nephrology (CIN), Department of Pediatrics, School of Medical Sciences (FCM), State University of Campinas, UNICAMP, Campinas, Brazil.,Department of Pediatrics, School of Medical Sciences (FCM), UNICAMP, Campinas, SP, Brazil
| | - Gil Guerra-Júnior
- Department of Pediatrics, School of Medical Sciences (FCM), UNICAMP, Campinas, SP, Brazil.,Growth and Development Laboratory, Center for Investigation in Pediatrics (CIPED), School of Medical Sciences (FCM), UNICAMP, Campinas, SP, Brazil
| | - Maricilda Palandi de Mello
- Laboratory of Human Molecular Genetics, Center for Molecular Biology and Genetic Engineering (CBMEG), State University of Campinas, UNICAMP, Caixa Postal 6010, 13083-875, Campinas, SP, Brazil
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9
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Abstract
Zusammenfassung
Das steroid-resistente nephrotische Syndrom (SRNS) mit dem histomorphologischen Korrelat der fokal-segmentalen Glomerulosklerose (FSGS) stellt eine bedeutende Ursache für eine terminale Niereninsuffizienz im Kindesalter, aber auch bei erwachsenen Patienten dar. Das Erkrankungsspektrum zeichnet sich durch eine große genetische Heterogenität aus, wobei auch nicht genetische Ursachen bei der FSGS beobachtet werden. Die genetische Grundlage des SRNS/FSGS-Komplexes ist v. a. für ältere Kinder/Jugendliche und Erwachsene bisher noch unzureichend verstanden. Die eindeutige Abgrenzung genetischer SRNS/FSGS-Ursachen ist unerlässlich, da sich bereits heute hieraus eine Vielzahl an klinischen Implikationen ergeben. Die Identifikation unbekannter Erkrankungsallele oder Erkrankungsgene kann zudem Erkenntnisse bringen, die ein gänzlich neues Verständnis der Pathomechanismen ermöglichen. Durch umfassende genetische Untersuchungen besteht die Möglichkeit, die ungelöste genetische Basis der Rekurrenz der FSGS-Erkrankung bei bislang Varianten-negativen Patienten zu finden.
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Affiliation(s)
- Julia Hoefele
- Aff1 Institut für Humangenetik Klinikum rechts der Isar, Technische Universität München Trogerstr. 32 81675 München Deutschland
| | - Bodo B. Beck
- Aff2 0000 0000 8852 305X grid.411097.a Institut für Humangenetik Uniklinik Köln Kerpener Str. 34 50937 Köln Deutschland
| | - Lutz T. Weber
- Aff3 0000 0000 8852 305X grid.411097.a Klinik und Poliklinik für Kinder- und Jugendmedizin Uniklinik Köln Kerpener Str. 62 50937 Köln Deutschland
| | - Paul Brinkkötter
- Aff4 0000 0000 8852 305X grid.411097.a Klinik II für Innere Medizin Uniklinik Köln Kerpener Str. 62 50937 Köln Deutschland
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10
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Siji A, Karthik KN, Pardeshi VC, Hari PS, Vasudevan A. Targeted gene panel for genetic testing of south Indian children with steroid resistant nephrotic syndrome. BMC MEDICAL GENETICS 2018; 19:200. [PMID: 30458709 PMCID: PMC6245897 DOI: 10.1186/s12881-018-0714-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Accepted: 11/07/2018] [Indexed: 01/10/2023]
Abstract
BACKGROUND Steroid resistant nephrotic syndrome (SRNS) is a genetically heterogeneous disease with significant phenotypic variability. More than 53 podocyte-expressed genes are implicated in SRNS which complicates the routine use of genetic screening in the clinic. Next generation sequencing technology (NGS) allows rapid screening of multiple genes in large number of patients in a cost-effective manner. METHODS We developed a targeted panel of 17 genes to determine relative frequency of mutations in south Indian ethnicity and feasibility of using the assay in a clinical setting. Twenty-five children with SRNS and 3 healthy individuals were screened. RESULTS In this study, novel variants including 1 pathogenic variant (2 patients) and 3 likely pathogenic variants (3 patients) were identified. In addition, 2 novel variants of unknown significance (VUS) in 2 patients (8% of total patients) were also identified. CONCLUSIONS The results show that genetic screening in SRNS using NGS is feasible in a clinical setting. However the panel needs to be screened in a larger cohort of children with SRNS in order to assess the utility of the customised targeted panel in Indian children with SRNS. Determining the prevalence of variants in Indian population and improvising the bioinformatics-based filtering strategy for a more accurate differentiation of pathogenic variants from those that are benign among the VUS will help in improving medical and genetic counselling in SRNS.
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Affiliation(s)
- Annes Siji
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - K N Karthik
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | | | - P S Hari
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India
| | - Anil Vasudevan
- Division of Molecular Medicine, St. John's Research Institute, Bangalore, India. .,Department of Pediatric Nephrology, St. John's Medical College Hospital, Bangalore, India.
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11
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Yu SMW, Nissaisorakarn P, Husain I, Jim B. Proteinuric Kidney Diseases: A Podocyte's Slit Diaphragm and Cytoskeleton Approach. Front Med (Lausanne) 2018; 5:221. [PMID: 30255020 PMCID: PMC6141722 DOI: 10.3389/fmed.2018.00221] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Accepted: 07/18/2018] [Indexed: 01/19/2023] Open
Abstract
Proteinuric kidney diseases are a group of disorders with diverse pathological mechanisms associated with significant losses of protein in the urine. The glomerular filtration barrier (GFB), comprised of the three important layers, the fenestrated glomerular endothelium, the glomerular basement membrane (GBM), and the podocyte, dictates that disruption of any one of these structures should lead to proteinuric disease. Podocytes, in particular, have long been considered as the final gatekeeper of the GFB. This specialized visceral epithelial cell contains a complex framework of cytoskeletons forming foot processes and mediate important cell signaling to maintain podocyte health. In this review, we will focus on slit diaphragm proteins such as nephrin, podocin, TRPC6/5, as well as cytoskeletal proteins Rho/small GTPases and synaptopodin and their respective roles in participating in the pathogenesis of proteinuric kidney diseases. Furthermore, we will summarize the potential therapeutic options targeting the podocyte to treat this group of kidney diseases.
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Affiliation(s)
- Samuel Mon-Wei Yu
- Department of Medicine, Jacobi Medical Center, Bronx, NY, United States
| | | | - Irma Husain
- Department of Medicine, James J. Peters VA Medical Center, Bronx, NY, United States
| | - Belinda Jim
- Department of Medicine, Jacobi Medical Center, Bronx, NY, United States.,Renal Division, Jacobi Medical Center, Bronx, NY, United States
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12
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Cyclosporine A responsive congenital nephrotic syndrome with single heterozygous variants in NPHS1, NPHS2, and PLCE1. Pediatr Nephrol 2018; 33:1269-1272. [PMID: 29663071 DOI: 10.1007/s00467-018-3961-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Revised: 03/26/2018] [Accepted: 04/03/2018] [Indexed: 10/17/2022]
Abstract
BACKGROUND Congenital nephrotic syndrome (CNS) is primarily a monogenetic disease, with the majority of cases due to changes in five different genes: the nephrin (NPHS1), podocin (NPHS2), Wilms tumor 1 (WT1), laminin ß2 (LAMB2), and phospholipase C epsilon 1 (PLCE1, NPHS3) gene. Usually CNS is not responsive to immunosuppressive therapy, but treatment with ACE inhibitors, AT1 receptor blockade and/or indomethacin can reduce proteinuria. If the disease progresses to end-stage renal disease, kidney transplantation is the therapy of choice. CASE-DIAGNOSIS Here, we present the case of a 4-month-old girl with congenital nephrotic syndrome. Upon admission, the patient presented with life-threatening anasarca, hypoalbuminemia, proteinuria, and impaired growth. There was no evidence of an infectious or immunological etiology. The genetic evaluation revealed a heterozygous variant in NPHS1 (p.Arg207Trp), in NPHS2 (p.Ser95Phe) as well as in PLCE1 (p.Ala1045Ser) and did not explain CNS. In addition to daily parenteral albumin infusions plus furosemide, a pharmacological antiproteinuric therapy was started to reduce protein excretion. Based on the genetic results, immunosuppressive therapy with prednisolone was initiated, but without response. However, following cyclosporine A treatment, the patient achieved complete remission and now has good renal function, growth, and development. CONCLUSIONS A profound search for the cause of CNS is necessary but has its limitations. The therapeutic strategy should be adapted when the etiology remains unclear.
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D'Argenio V. The High-Throughput Analyses Era: Are We Ready for the Data Struggle? High Throughput 2018; 7:E8. [PMID: 29498666 PMCID: PMC5876534 DOI: 10.3390/ht7010008] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2017] [Revised: 02/16/2018] [Accepted: 02/27/2018] [Indexed: 12/23/2022] Open
Abstract
Recent and rapid technological advances in molecular sciences have dramatically increased the ability to carry out high-throughput studies characterized by big data production. This, in turn, led to the consequent negative effect of highlighting the presence of a gap between data yield and their analysis. Indeed, big data management is becoming an increasingly important aspect of many fields of molecular research including the study of human diseases. Now, the challenge is to identify, within the huge amount of data obtained, that which is of clinical relevance. In this context, issues related to data interpretation, sharing and storage need to be assessed and standardized. Once this is achieved, the integration of data from different -omic approaches will improve the diagnosis, monitoring and therapy of diseases by allowing the identification of novel, potentially actionably biomarkers in view of personalized medicine.
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Affiliation(s)
- Valeria D'Argenio
- CEINGE-Biotecnologie Avanzate, via G. Salvatore 486, 80145 Naples, Italy.
- Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, via Pansini 5, 80131 Naples, Italy.
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De Vriese AS, Sethi S, Nath KA, Glassock RJ, Fervenza FC. Differentiating Primary, Genetic, and Secondary FSGS in Adults: A Clinicopathologic Approach. J Am Soc Nephrol 2018; 29:759-774. [PMID: 29321142 DOI: 10.1681/asn.2017090958] [Citation(s) in RCA: 186] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
FSGS describes a renal histologic lesion with diverse causes and pathogenicities that are linked by podocyte injury and depletion. Subclasses of FSGS include primary, genetic, and secondary forms, the latter comprising maladaptive, viral, and drug-induced FSGS. Despite sharing certain clinical and histologic features, these subclasses differ noticeably in management and prognosis. Without an accepted nongenetic biomarker that discriminates among these FSGS types, classification of patients is often challenging. This review summarizes the clinical and histologic features, including the onset and severity of proteinuria as well as the presence of nephrotic syndrome, that may aid in identifying the specific FSGS subtype. The FSGS lesion is characterized by segmental sclerosis and must be differentiated from nonspecific focal global glomerulosclerosis. No light microscopic features are pathognomonic for a particular FSGS subcategory. The characteristics of podocyte foot process effacement on electron microscopy, while helpful in discriminating between primary and maladaptive FSGS, may be of little utility in detecting genetic forms of FSGS. When FSGS cannot be classified by clinicopathologic assessment, genetic analysis should be offered. Next generation DNA sequencing enables cost-effective screening of multiple genes simultaneously, but determining the pathogenicity of a detected genetic variant may be challenging. A more systematic evaluation of patients, as suggested herein, will likely improve therapeutic outcomes and the design of future trials in FSGS.
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Affiliation(s)
- An S De Vriese
- Division of Nephrology, AZ Sint-Jan Brugge-Oostende, Brugge, Belgium;
| | | | - Karl A Nath
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; and
| | - Richard J Glassock
- Geffen School of Medicine at the University of California, Los Angeles, California
| | - Fernando C Fervenza
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; and
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Application of next-generation sequencing technology to diagnosis and treatment of focal segmental glomerulosclerosis. Clin Exp Nephrol 2017; 22:491-500. [PMID: 28752288 PMCID: PMC5956018 DOI: 10.1007/s10157-017-1449-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Accepted: 07/06/2017] [Indexed: 12/15/2022]
Abstract
A broad range of genetic and non-genetic factors can lead to kidney injury that manifests as focal segmental glomerulosclerosis (FSGS), which can be classified into primary (idiopathic) and secondary forms. Previous genetic approaches to familial or sporadic cases of FSGS or steroid-resistant nephrotic syndrome identified causal mutations in a subset of genes. Recently, next-generation sequencing (NGS) approaches are becoming a part of a standard assessment in medical genetics. Current knowledge of the comprehensive genomic information is changing the way we think about FSGS and draws attention not only to identification of novel causal genes, but also to potential roles for combinations of mutations in multiple genes, mutations with complex inheritance, and susceptibility genes with variable penetrance carrying relatively minor but significant effects. This review provides an update on recent advances in the genetic analysis of FSGS and highlights the potential as well as the new challenges of NGS for diagnosis and mechanism-based treatment of FSGS.
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Crawford BD, Gillies CE, Robertson CC, Kretzler M, Otto EA, Vega-Warner V, Sampson MG. Evaluating Mendelian nephrotic syndrome genes for evidence for risk alleles or oligogenicity that explain heritability. Pediatr Nephrol 2017; 32:467-476. [PMID: 27766458 PMCID: PMC5483602 DOI: 10.1007/s00467-016-3513-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 08/25/2016] [Accepted: 08/29/2016] [Indexed: 01/08/2023]
Abstract
BACKGROUND More than 30 genes can harbor rare exonic variants sufficient to cause nephrotic syndrome (NS), and the number of genes implicated in monogenic NS continues to grow. However, outside the first year of life, the majority of affected patients, particularly in ancestrally mixed populations, do not have a known monogenic form of NS. Even in those children classified with a monogenic form of NS, there is phenotypic heterogeneity. Thus, we have only discovered a fraction of the heritability of NS-the underlying genetic factors contributing to phenotypic variation. Part of the "missing heritability" for NS has been posited to be explained by patients harboring coding variants across one or more previously implicated NS genes, insufficient to cause NS in a classical Mendelian manner, but that nonetheless have a sufficient impact on protein function to cause disease. However, systematic evaluation in patients with NS for rare or low-frequency risk alleles within single genes, or in combination across genes ("oligogenicity"), has not been reported. To determine whether, compared with a reference population, patients with NS have either a significantly increased burden of protein-altering variants ("risk-alleles"), or a unique combination of them ("oligogenicity"), in a set of 21 genes implicated in Mendelian forms of NS. METHODS In 303 patients with NS enrolled in the Nephrotic Syndrome Study Network (NEPTUNE), we performed targeted amplification paired with next-generation sequencing of 21 genes implicated in monogenic NS. We created a high-quality variant call set and compared it with a variant call set of the same genes in a reference population composed of 2,535 individuals from phase 3 of the 1000 Genomes Project. We created both a "stringent" and a "relaxed" pathogenicity-filtering pipeline, applied them to both cohorts, and computed the burden of variants in the entire gene set per cohort, the burden of variants in the entire gene set per individual, the burden of variants within a single gene per cohort, and unique combinations of variants across two or more genes per cohort. RESULTS With few exceptions when using the relaxed filter, and which are likely the result of confounding by population stratification, NS patients did not have a significantly increased burden of variants in Mendelian NS genes in comparison to a reference cohort, nor was there any evidence for oligogenicity. This was true when using both the relaxed and the stringent variant pathogenicity filter. CONCLUSION In our study, there were no significant differences in the burden or particular combinations of low-frequency or rare protein-altering variants in a previously implicated Mendelian NS genes cohort between North American patients with NS and a reference population. Studies in larger independent cohorts or meta-analyses are needed to assess the generalizability of our discoveries and also address whether there is in fact small but significant enrichment of risk alleles or oligogenicity in NS cases that was undetectable with this current sample size. It is still possible that rare protein-altering variants in these genes, insufficient to cause Mendelian disease, still contribute to NS as risk alleles and/or via oligogenicity. However, we suggest that more accurate bioinformatic analyses and the incorporation of functional assays would be necessary to identify bona fide instances of this form of genetic architecture as a contributor to the heritability of NS.
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Affiliation(s)
- Brendan D Crawford
- Department of Pediatrics, University of Michigan Medical School, 3560B MSRB 2, Ann Arbor, MI, USA
| | - Christopher E Gillies
- Department of Pediatrics, University of Michigan Medical School, 3560B MSRB 2, Ann Arbor, MI, USA
| | - Catherine C Robertson
- Department of Pediatrics, University of Michigan Medical School, 3560B MSRB 2, Ann Arbor, MI, USA
| | - Matthias Kretzler
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Edgar A Otto
- Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Virginia Vega-Warner
- Department of Pediatrics, University of Michigan Medical School, 3560B MSRB 2, Ann Arbor, MI, USA
| | - Matthew G Sampson
- Department of Pediatrics, University of Michigan Medical School, 3560B MSRB 2, Ann Arbor, MI, USA.
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Hoefele J, Kemper MJ, Schoenermarck U, Mueller S, Klein HG, Lemke A. Truncating Wilms Tumor Suppressor Gene 1 Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report. Nephron Clin Pract 2016; 135:72-76. [PMID: 27701157 DOI: 10.1159/000450709] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Accepted: 09/01/2016] [Indexed: 11/19/2022] Open
Abstract
About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372C>T (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868G>A (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.
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Affiliation(s)
- Julia Hoefele
- Institute of Human Genetics, Technical University Munich, Munich, Germany
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