A Novel Hybrid CFHR1/CFH Gene Causes Atypical Hemolytic Uremic Syndrome

Stephen J Eyler; Nicole C Meyer; Yuzhou Zhang; Xue Xiao; Carla M Nester; Richard J.H Smith

doi:10.1007/s00467-013-2560-2

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A Novel Hybrid CFHR1/CFH Gene Causes Atypical Hemolytic Uremic Syndrome

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A Novel Hybrid CFHR1/CFH Gene Causes Atypical Hemolytic Uremic Syndrome

Stephen J Eyler, Nicole C Meyer, Yuzhou Zhang, Xue Xiao, Carla M Nester and Richard J.H Smith

Pediatric nephrology (Berlin, West), Vol.28(11), pp.2221-2225

11/2013

DOI: 10.1007/s00467-013-2560-2

PMCID: PMC4433496

PMID: 23880784

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Abstract

Background Mutations in complement factor H (CFH) are associated with complement dysregulation and the development of an aggressive form of atypical hemolytic uremic syndrome (aHUS) that progresses to end-stage renal disease (ESRD) and in most patients has a high rate of recurrence following transplantation. Sequence analysis of CFH and its downstream complement factor H-related genes (CFHR1-5) reveals several macrohomologous blocks caused by large genomic duplications. This high degree of sequence identity renders this area susceptible to nonallelic homologous recombination (NAHR) events, resulting in large-scale deletions, duplications, and the generation of hybrid CFH genes. Case-Diagnosis Here, we report the finding of a novel CFHR1/CFH hybrid gene created by a de novo NAHR event in a 14-year-old girl with aHUS. The resulting fusion protein contains the first three short consensus repeats (SCRs) of CFHR1 and the terminal two SCRs of CFH. Conclusions This finding demonstrates a novel pathogenic mechanism for the development of aHUS. Additionally, since standard Sanger sequencing is unable to detect such rearrangements, all aHUS patients should receive comprehensive genetic screening that includes analysis of copy number variation in order to identify patients with poor clinical prognoses.

Atypical hemolytic uremic syndrome

nonallelic homologous recombination

factor H hybrid genes

alternative pathway of complement

Details

Title: Subtitle: A Novel Hybrid CFHR1/CFH Gene Causes Atypical Hemolytic Uremic Syndrome
Creators: Stephen J Eyler - Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Nicole C Meyer - Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Yuzhou Zhang - Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Xue Xiao - Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Carla M Nester - Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Richard J.H Smith - Molecular Otolaryngology and Renal Research Laboratories, Divisions of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
Resource Type: Journal article
Publication Details: Pediatric nephrology (Berlin, West), Vol.28(11), pp.2221-2225
DOI: 10.1007/s00467-013-2560-2
PMID: 23880784
PMCID: PMC4433496
NLM abbreviation: Pediatr Nephrol
ISSN: 0931-041X
eISSN: 1432-198X
Language: English
Date published: 11/2013
Academic Unit: 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; Otolaryngology; Internal Medicine
Record Identifier: 9984007291502771

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