title: Familial C3 glomerulonephritis caused by a novel CFHR5-CFHR2 fusion gene.
abstract: 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.
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA; Interdepartmental PhD Program in Genetics, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Medicine, Division of Nephrology and Hypertension Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Cybele
authors.initials: C
authors.lastname: Ghossein
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain.
authors.forename: Agustín
authors.initials: A
authors.lastname: Tortajada
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Meyer
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Jones
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Nicolo Ghiringhelli
authors.initials: NG
authors.lastname: Borsa
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA; Departments of Pediatrics and Internal Medicine, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Carla M
authors.initials: CM
authors.lastname: Nester
authors.affiliation: Departments of Pediatrics and Internal Medicine, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Institute of Human Genetics, Caver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Christie P
authors.initials: CP
authors.lastname: Thomas
authors.affiliation: Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas and Centro de Investigación Biomédica en Enfermedades Raras, Madrid, Spain.
authors.forename: Santiago Rodríquez
authors.initials: SR
authors.lastname: de Córdoba
authors.affiliation: Molecular Otolaryngology and Renal Research Laboratories, Caver College of Medicine, University of Iowa, Iowa City, IA, USA; Interdepartmental PhD Program in Genetics, Caver College of Medicine, University of Iowa, Iowa City, IA, USA; Departments of Pediatrics and Internal Medicine, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; Iowa Institute of Human Genetics, Caver College of Medicine, University of Iowa, Iowa City, IA, USA. Electronic address: richard-smith@uiowa.edu.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D000328:Adult; D015153:Blotting, Western; D055028:Comparative Genomic Hybridization; D003180:Complement C3b Inactivator Proteins / Q000235:genetics*; D003165:Complement System Proteins / Q000235:genetics*; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics*; D006801:Humans; D008297:Male; D060885:Multiplex Polymerase Chain Reaction; D010375:Pedigree
chemical_list: C586681:CFHR2 protein, human; C432223:CFHR5 protein, human; D003180:Complement C3b Inactivator Proteins; D003165:Complement System Proteins
keywords: C3 glomerulopathy; Complement factor H related-2; Complement factor H related-5