Journal article
Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy
The Journal of immunology (1950), Vol.200(7), pp.2464-2478
04/01/2018
DOI: 10.4049/jimmunol.1701695
PMCID: PMC6324840
PMID: 29500241
Abstract
Atypical hemolytic uremic syndrome (aHUS) and C3 glomerulopathy (C3G) are associated with dysregulation and overactivation of the complement alternative pathway. Typically, gene analysis for aHUS and C3G is undertaken in small patient numbers, yet it is unclear which genes most frequently predispose to aHUS or C3G. Accordingly, we performed a six-center analysis of 610 rare genetic variants in 13 mostly complement genes (
,
,
,
,
,
,
,
,
,
,
,
, and
) from >3500 patients with aHUS and C3G. We report 371 novel rare variants (RVs) for aHUS and 82 for C3G. Our new interactive Database of Complement Gene Variants was used to extract allele frequency data for these 13 genes using the Exome Aggregation Consortium server as the reference genome. For aHUS, significantly more protein-altering rare variation was found in five genes
,
,
,
, and
than in the Exome Aggregation Consortium (allele frequency < 0.01%), thus correlating these with aHUS. For C3G, an association was only found for RVs in
and the N-terminal C3b-binding or C-terminal nonsurface-associated regions of
In conclusion, the RV analyses showed nonrandom distributions over the affected proteins, and different distributions were observed between aHUS and C3G that clarify their phenotypes.
Details
- Title: Subtitle
- Statistical Validation of Rare Complement Variants Provides Insights into the Molecular Basis of Atypical Hemolytic Uremic Syndrome and C3 Glomerulopathy
- Creators
- Amy J Osborne - Department of Structural and Molecular Biology, University College London, London WC1E 6BT, United KingdomMatteo Breno - Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," 24020 Ranica Bergamo, ItalyNicolo Ghiringhelli Borsa - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Fengxiao Bu - Medical Genetics Center, Southwest Hospital, Chongqing 400038, ChinaVéronique Frémeaux-Bacchi - Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, 75015 Paris, FranceDaniel P Gale - Centre for Nephrology, Royal Free Hospital, University College London, London NW3 2QG, United KingdomLambertus P van den Heuvel - Department of Pediatric Nephrology, Department of Growth and Regeneration, University Hospital Leuven, 3000 Leuven, BelgiumDavid Kavanagh - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United KingdomMarina Noris - Centro di Ricerche Cliniche per le Malattie Rare "Aldo e Cele Daccò," IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri," 24020 Ranica Bergamo, ItalySheila Pinto - Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, 28040 Madrid, SpainPavithra M Rallapalli - Department of Structural and Molecular Biology, University College London, London WC1E 6BT, United KingdomGiuseppe Remuzzi - Department of Biomedical and Clinical Sciences, University of Milan, 20122 Milan, Italy; andSantiago Rodriguez de Cordoba - Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, 28040 Madrid, SpainAngela Ruiz - Department of Cellular and Molecular Medicine, Center for Biological Research and Center for Biomedical Network Research on Rare Diseases, 28040 Madrid, SpainRichard J H Smith - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, IA 52242Paula Vieira-Martins - Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service d'Immunologie Biologique, 75015 Paris, FranceElena Volokhina - Department of Pediatric Nephrology, Radboud University Medical Center, 6525 GA Nijmegen, the NetherlandsValerie Wilson - Northern Molecular Genetics Service, Newcastle upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne NE1 3BZ, United KingdomTimothy H J Goodship - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United KingdomStephen J Perkins - Department of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom; s.perkins@ucl.ac.uk
- Resource Type
- Journal article
- Publication Details
- The Journal of immunology (1950), Vol.200(7), pp.2464-2478
- DOI
- 10.4049/jimmunol.1701695
- PMID
- 29500241
- PMCID
- PMC6324840
- NLM abbreviation
- J Immunol
- ISSN
- 1550-6606
- eISSN
- 1550-6606
- Publisher
- United States
- Grant note
- G1002528 / Medical Research Council R01 DK110023 / NIDDK NIH HHS MR/K011715/1 / Medical Research Council
- Language
- English
- Date published
- 04/01/2018
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
- Record Identifier
- 9984007294002771
Metrics
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