A De Novo Deletion in the Regulators of Complement Activation Cluster Producing a Hybrid Complement Factor H/Complement Factor H-Related 3 Gene in Atypical Hemolytic Uremic Syndrome.
The regulators of complement activation cluster at chromosome 1q32 contains the complement factor H (CFH) and five complement factor H-related (CFHR) genes. This area of the genome arose from several large genomic duplications, and these low-copy repeats can cause genome instability in this region. Genomic disorders affecting these genes have been described in atypical hemolytic uremic syndrome, arising commonly through nonallelic homologous recombination. We describe a novel CFH/CFHR3 hybrid gene secondary to a de novo 6.3-kb deletion that arose through microhomology-mediated end joining rather than nonallelic homologous recombination. We confirmed a transcript from this hybrid gene and showed a secreted protein product that lacks the recognition domain of factor H and exhibits impaired cell surface complement regulation. The fact that the formation of this hybrid gene arose as a de novo event suggests that this cluster is a dynamic area of the genome in which additional genomic disorders may arise.
Institutes of Genetic Medicine and.
Rachel C
RC
Challis
Institutes of Genetic Medicine and.
Geisilaine S R
GS
Araujo
Institutes of Genetic Medicine and.
Edwin K S
EK
Wong
Institutes of Genetic Medicine and.
Holly E
HE
Anderson
Department of Nephrology, Our Lady's Children's Hospital, Crumlin, Dublin;
Atif
A
Awan
Department of Renal Pathology, Beaumont Hospital, Royal College of Surgeons in Ireland, Dublin, Ireland; and.
Anthony M
AM
Dorman
Department of Nephrology, Our Lady's Children's Hospital, Crumlin, Dublin;
Mary
M
Waldron
Institutes of Genetic Medicine and.
Valerie
V
Wilson
Institutes of Genetic Medicine and.
Vicky
V
Brocklebank
Institutes of Genetic Medicine and.
Lisa
L
Strain
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
B Paul
BP
Morgan
Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom.
Claire L
CL
Harris
Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
Kevin J
KJ
Marchbank
Institutes of Genetic Medicine and.
Timothy H J
TH
Goodship
Institutes of Genetic Medicine and david.kavanagh@ncl.ac.uk.
David
D
Kavanagh
D000818:Animals; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics*; D001798:Blood Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003167:Complement Activation / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D017353:Gene Deletion; D006801:Humans; D012756:Sheep
D001798:Blood Proteins; C493495:CFH protein, human; C105970:CFHR3 protein, human; D017242:Complement Factor H
complement; genetic renal disease; hemolytic uremic syndrome