A novel hybrid CFHR1/CFH gene causes atypical hemolytic uremic syndrome

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 trans...

Full description

Saved in:
Bibliographic Details
Published in:Pediatric nephrology (Berlin, West) West), 2013-11, Vol.28 (11), p.2221-2225
Main Authors: Eyler, Stephen J., Meyer, Nicole C., Zhang, Yuzhou, Xiao, Xue, Nester, Carla M., Smith, Richard J. H.
Format: Article
Language:English
Subjects:
Anemia
Antibodies, Monoclonal, Humanized - therapeutic use
Autoantibodies - analysis
Blotting, Western
Brief Report
Case studies
Child
Complement C3b Inactivator Proteins - genetics
Complement factor H
Complement Factor H - genetics
Creatinine - blood
Diagnosis
DNA - genetics
Female
Gene Amplification
Gene mutations
Genes
Genetic aspects
Hemodialysis
Hemoglobin
Hemolytic-uremic syndrome
Hemolytic-Uremic Syndrome - genetics
Humans
Hypertension
Immunosuppressive Agents - therapeutic use
Kidney diseases
Kidney Transplantation
Kidney transplants
Kidneys
Medicine
Medicine & Public Health
Mutation
Nephrology
Patients
Pediatrics
Polymerase Chain Reaction
Properties
Renal Dialysis
Transplantation
Urology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0931-041X
1432-198X
DOI:10.1007/s00467-013-2560-2