title: A novel hybrid CFH/CFHR3 gene generated by a microhomology-mediated deletion in familial atypical hemolytic uremic syndrome.
abstract: Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomology-mediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with normal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule.
authors: Department of Infection, Immunity & Biochemistry, Cardiff University School of Medicine, Heath Park, United Kingdom.
authors: Nigel J
authors: NJ
authors: Francis
authors: Bairbre
authors: B
authors: McNicholas
authors: Atif
authors: A
authors: Awan
authors: Mary
authors: M
authors: Waldron
authors: Donal
authors: D
authors: Reddan
authors: Denise
authors: D
authors: Sadlier
authors: David
authors: D
authors: Kavanagh
authors: Lisa
authors: L
authors: Strain
authors: Kevin J
authors: KJ
authors: Marchbank
authors: Claire L
authors: CL
authors: Harris
authors: Timothy H J
authors: TH
authors: Goodship
mesh_terms: D000818:Animals; D001053:Apolipoproteins / Q000235:genetics* / Q000378:metabolism; D065766:Atypical Hemolytic Uremic Syndrome; D001323:Autoantibodies; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D003167:Complement Activation; D003180:Complement C3b Inactivator Proteins / Q000235:genetics* / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics* / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006461:Hemolysis; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D059765:Homologous Recombination; D006801:Humans; D008969:Molecular Sequence Data; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D012689:Sequence Homology, Nucleic Acid; D012756:Sheep; D020349:Surface Plasmon Resonance
chemical_list: D001053:Apolipoproteins; D001323:Autoantibodies; D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; C105092:CFHR4 protein, human; D003180:Complement C3b Inactivator Proteins; D050506:Mutant Chimeric Proteins; D017242:Complement Factor H