title: Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome.
abstract: Atypical hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. Disease-associated mutations have been described in the genes encoding the complement regulators complement factor H, membrane cofactor protein, factor B, and factor I. In this study, we show in two independent cohorts of aHUS patients that deletion of two closely related genes, complement factor H-related 1 (CFHR1) and complement factor H-related 3 (CFHR3), increases the risk of aHUS. Amplification analysis and sequencing of genomic DNA of three affected individuals revealed a chromosomal deletion of approximately 84 kb in the RCA gene cluster, resulting in loss of the genes coding for CFHR1 and CFHR3, but leaving the genomic structure of factor H intact. The CFHR1 and CFHR3 genes are flanked by long homologous repeats with long interspersed nuclear elements (retrotransposons) and we suggest that nonallelic homologous recombination between these repeats results in the loss of the two genes. Impaired protection of erythrocytes from complement activation is observed in the serum of aHUS patients deficient in CFHR1 and CFHR3, thus suggesting a regulatory role for CFHR1 and CFHR3 in complement activation. The identification of CFHR1/CFHR3 deficiency in aHUS patients may lead to the design of new diagnostic approaches, such as enhanced testing for these genes.
authors: Leibniz Institute for Natural Product Research and Infection Biology, Hans Knoell Institute, Jena, Germany.
authors: Peter F
authors: PF
authors: Zipfel
authors: Matthew
authors: M
authors: Edey
authors: Stefan
authors: S
authors: Heinen
authors: Mihály
authors: M
authors: Józsi
authors: Heiko
authors: H
authors: Richter
authors: Joachim
authors: J
authors: Misselwitz
authors: Bernd
authors: B
authors: Hoppe
authors: Danny
authors: D
authors: Routledge
authors: Lisa
authors: L
authors: Strain
authors: Anne E
authors: AE
authors: Hughes
authors: Judith A
authors: JA
authors: Goodship
authors: Christoph
authors: C
authors: Licht
authors: Timothy H J
authors: TH
authors: Goodship
authors: Christine
authors: C
authors: Skerka
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001798:Blood Proteins / Q000172:deficiency / Q000235:genetics*; D016022:Case-Control Studies; D002877:Chromosomes, Human / Q000235:genetics; D003180:Complement C3b Inactivator Proteins / Q000172:deficiency / Q000235:genetics*; D017242:Complement Factor H / Q000172:deficiency / Q000235:genetics*; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D005787:Gene Frequency; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D005810:Multigene Family
chemical_list: D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H