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Impact of compound heterozygous complement factor H mutations on development of atypical hemolytic uremic syndrome-A pedigree revisited

Lookup NU author(s): Professor Kevin MarchbankORCiD, Professor Tim Goodship


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Atypical hemolytic uremic syndrome (aHUS) is associated with mutations in the gene CFH encoding the complement regulator factor H (CFH). We previously reported a family, in which three individuals had partial CFH deficiency but only one was affected by aHUS. We have investigated this family further to show that the partial CFH deficiency is associated with a heterozygous CFH mutation (c.2768T>G, p.Tyr899Asp). We used the polymorphic CFH variant p.His402Tyr to track expression of p.Tyr899Asp, and found that this mutant was expressed in minimal quantities in serum. In the one affected individual we found a second CFH mutation (c.3581G>A, p.Gly1194Asp) on the other allele which was expressed normally. We showed that this mutant, which has been described previously in aHUS, has impaired regulation of cell surface complement activation. The affected individual in this family is therefore a compound heterozygote for two functionally significant CFH mutations. Two individuals (mother and male sib) in the pedigree carried only c.2768T>G, p.Tyr899Asp and one (father) carried only c.3581G>A, p.Gly1194Asp, and all three were asymptomatic. Thus, further investigation of this family has enabled us to clarify the genotype-phenotype correlation. (C) 2010 Published by Elsevier Ltd.

Publication metadata

Author(s): Johnson SA, Williams JM, Hakobyan S, Richards A, Perkins SJ, Marchbank KJ, Goodship THJ, Morgan BP, Taylor CM, Savage COS

Publication type: Article

Publication status: Published

Journal: Molecular Immunology

Year: 2010

Volume: 47

Issue: 7-8

Pages: 1585-1591

Print publication date: 01/04/2010

ISSN (print): 0161-5890

ISSN (electronic): 1872-9142

Publisher: Pergamon


DOI: 10.1016/j.molimm.2009.12.001


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Funder referenceFunder name
068590Wellcome Trust
BCHRF053Birmingham Children's Hospital Research Foundation
G0701325UK Medical Research Council
RTF1158Action Medical Research