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Atypical haemolytic uraemic syndrome associated with a hybrid complement gene

Lookup NU author(s): Dr Julian Venables, Dr Lisa Turnbull, Dr David Bourn, Dr Martha Lucia Diaz Torres, Dr Michael Jackson, Professor Judith Goodship, Professor Tim Goodship

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Abstract

Background: Sequence analysis of the regulators of complement activation (RCA) cluster of genes at chromosome position 1q32 shows evidence of several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for factor H (CFH) and the genes for the five factor H-related proteins (CFHL1-5; aliases CFHR1-5). CFH mutations have been described in association with atypical haemolytic uraemic syndrome (aHUS). The majority of the mutations are missense changes that cluster in the C-terminal region and impair the ability of factor H to regulate surface-bound C3b. Some have arisen as a result of gene conversion between CFH and CFHL1. In this study we tested the hypothesis that nonallelic homologous recombination between low-copy repeats in the RCA cluster could result in the formation of a hybrid CFH/CFHL1 gene that predisposes to the development of aHUS. Methods and Findings: In a family with many cases of aHUS that segregate with the RCA cluster we used cDNA analysis, gene sequencing, and Southern blotting to show that affected individuals carry a heterozygous CFH/CFHL1 hybrid gene in which exons 1-21 are derived from CFH and exons 22/23 from CFHL1. This hybrid encodes a protein product identical to a functionally significant CFH mutant (c.3572C>T, S1191L and c.3590T>C, V1197A) that has been previously described in association with aHUS. Conclusions: CFH mutation screening is recommended in all aHUS patients prior to renal transplantation because of the high risk of disease recurrence post-transplant in those known to have a CFH mutation. Because of our finding it will be necessary to implement additional screening strategies that will detect a hybrid CFH/CFHL1 gene. © 2006 Venables et al.


Publication metadata

Author(s): Venables JP, Strain L, Routledge D, Bourn D, Powell HM, Warwicker P, Diaz-Torres ML, Sampson A, Mead P, Webb M, Pirson Y, Jackson MS, Hughes A, Wood KM, Goodship JA, Goodship THJ

Publication type: Article

Publication status: Published

Journal: PLoS Medicine

Year: 2006

Volume: 3

Issue: 10

Pages: e431 (1957-1967)

Print publication date: 01/10/2006

ISSN (print): 1549-1277

ISSN (electronic): 1549-1676

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pmed.0030431

DOI: 10.1371/journal.pmed.0030431


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