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Lookup NU author(s): Dr Matthew Edey, Dr Lisa Turnbull, Professor Judith Goodship, Professor Tim Goodship
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 ∼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. © 2007 Zipfel et al.
Author(s): Zipfel PF, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, Hoppe B, Routledge D, Strain L, Hughes AE, Goodship JA, Licht C, Goodship THJ, Skerka C
Publication type: Article
Publication status: Published
Journal: PLoS Genetics
Year: 2007
Volume: 3
Issue: 3
Pages: 0387-0392
Print publication date: 01/03/2007
ISSN (print): 1553-7390
ISSN (electronic): 1553-7404
Publisher: Public Library of Science
URL: http://dx.doi.org/10.1371/journal.pgen.0030041
DOI: 10.1371/journal.pgen.0030041
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