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- Title
Atypical haemolytic uraemic syndrome associated with a hybrid complement gene.
- Authors
Venables, Julian P; Strain, Lisa; Routledge, Danny; Bourn, David; Powell, Helen M; Warwicker, Paul; Diaz-Torres, Martha L; Sampson, Anne; Mead, Paul; Webb, Michelle; Pirson, Yves; Jackson, Michael S; Hughes, Anne; Wood, Katrina M; Goodship, Judith A; Goodship, Timothy H J
- Abstract
<bold>Background: </bold>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.<bold>Methods and Findings: </bold>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.<bold>Conclusions: </bold>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.
- Subjects
PROTEINS; NUCLEOTIDE separation; RESEARCH; COMPLEMENT (Immunology); SEQUENCE analysis; DNA; RESEARCH methodology; MEDICAL cooperation; EVALUATION research; IMMUNOBLOTTING; COMPARATIVE studies; GENOTYPES; DISEASE susceptibility; HEMOLYTIC-uremic syndrome; POLYMERASE chain reaction; NUCLEIC acid amplification techniques
- Publication
PLoS Medicine, 2006, Vol 3, Issue 10, pe431
- ISSN
1549-1277
- Publication type
journal article
- DOI
10.1371/journal.pmed.0030431