Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome

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 indepen...

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Published in:	PLoS genetics 2007-03, Vol.3 (3), p.e41-e41
Main Authors:	Zipfel, Peter F, Edey, Matthew, Heinen, Stefan, Józsi, Mihály, Richter, Heiko, Misselwitz, Joachim, Hoppe, Bernd, Routledge, Danny, Strain, Lisa, Hughes, Anne E, Goodship, Judith A, Licht, Christoph, Goodship, Timothy H J, Skerka, Christine
Format:	Article
Language:	eng
Subjects:	Adolescent Adult Base Sequence Binding sites Blood Proteins - deficiency Blood Proteins - genetics Case-Control Studies Chromosome deletion Chromosomes Chromosomes, Human - genetics Complement C3b Inactivator Proteins - deficiency Complement C3b Inactivator Proteins - genetics Complement Factor H - deficiency Complement Factor H - genetics Diagnosis Exons - genetics Gene Deletion Gene Dosage Gene Frequency Gene mutations Gene Rearrangement Genes Genetic aspects Genetic Predisposition to Disease Genetic susceptibility Genetics Genetics and Genomics Hemolytic-uremic syndrome Hemolytic-Uremic Syndrome - genetics Homo (Human) Humans Immunology Molecular Sequence Data Multigene Family Mutation Proteins Regulation Risk factors
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Summary:	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.
ISSN:	1553-7404 1553-7390 1553-7404