Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene

Xue Xiao; Cybele Ghossein; Agustín Tortajada; Yuzhou Zhang; Nicole Meyer; Michael Jones; Nicolo Ghiringhelli Borsa; Carla M Nester; Christie P Thomas; Santiago Rodríquez de Córdoba; Richard J.H Smith

doi:10.1016/j.molimm.2016.07.007

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Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene

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Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene

Xue Xiao, Cybele Ghossein, Agustín Tortajada, Yuzhou Zhang, Nicole Meyer, Michael Jones, Nicolo Ghiringhelli Borsa, Carla M Nester, Christie P Thomas, Santiago Rodríquez de Córdoba, …

Molecular immunology, Vol.77, pp.89-96

09/2016

DOI: 10.1016/j.molimm.2016.07.007

PMID: 27490940

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Abstract

•A novel CFHR5–CFHR2 fusion gene was identified as a cause of familial C3GN.•The fusion gene segregates with disease and is translated to a novel serum protein comprised of a portion of factor H related-5 and all of factor H related-2.•The novel protein forms multimers with factor H related-1, factor H related-5 and factor H-related-2 and alters complement activity. C3 glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized histologically by the predominance of C3 deposition within in the glomerulus. Familial cases of C3G are extremely uncommon and offer unique insight into the genetic drivers of complement dysregulation. In this report, we describe a patient who presented with C3G. Because a relative carried the same diagnosis, we sought an underlying genetic commonality to explain the phenotype. As part of a comprehension genetic screen, we completed multiplex ligation-dependent probe amplification across the complement factor H related region and identified amplification alterations consistent with a genomic rearrangement. Using comparative genomic hybridization, we narrowed and then cloned the rearrangement breakpoints thereby defining a novel fusion gene that is translated into a serum protein comprised of factor H related-5 (short consensus repeats 1 and 2) and factor H-related-2 (short consensus repeats 1–4). These data highlight the role of factor H related proteins in the control of complement activity and illustrate how perturbation of that control leads to C3G.

Complement factor H related-5

Complement factor H related-2

C3 glomerulopathy

Details

Title: Subtitle: Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene
Creators: Xue Xiao - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Cybele Ghossein - Department of Medicine, Division of Nephrology and Hypertension Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Agustín Tortajada - Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Nicole Meyer - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Michael Jones - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Nicolo Ghiringhelli Borsa - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Carla M Nester - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Christie P Thomas - Departments of Pediatrics and Internal Medicine, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Santiago Rodríquez de Córdoba - Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain
Richard J.H Smith - Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Molecular immunology, Vol.77, pp.89-96
DOI: 10.1016/j.molimm.2016.07.007
PMID: 27490940
NLM abbreviation: Mol Immunol
ISSN: 0161-5890
eISSN: 1872-9142
Publisher: Elsevier Ltd
Grant note: DOI: 10.13039/501100003329, name: Spanish “Ministerio de Economía y Competitividad”, award: SAF2011-26583; name: Fundación Renal Iñigo Alvarez de Toledo; name: Seventh Framework Programme European Union Project EURenOmics, award: 305608; name: Autonomous Region of Madrid, award: S2010/BMD-2316
Language: English
Date published: 09/2016
Academic Unit: Statistics and Actuarial Science; Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Nephrology, Dialysis and Transplantation; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biostatistics; Obstetrics and Gynecology; Public Policy Center (Archive); Otolaryngology; Internal Medicine
Record Identifier: 9983985902702771

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