Human Molecular Genetics Advance Access originally published online on January 20, 2005
Human Molecular Genetics 2005 14(5):703-712; doi:10.1093/hmg/ddi066
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Human Molecular Genetics, Vol. 14, No. 5 © Oxford University Press 2005; all rights reserved
Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32
1Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu 9, 28040 Madrid, Spain, 2Unidad de Hemostasia i Trombosis, Hospital de la Santa Creu i Sant Pau, Sant Antoni Ma Claret 167, 08025 Barcelona, Spain, 3Servicio de Nefrología, Hospital Universitario de Bellvitge, Feixa Llarga s/n, 08907 Barcelona, Spain and 4Unidad de Inmunología, Hospital Universitario La Paz, Paseo de la Castellana 261, 28046 Madrid, Spain
* To whom correspondence should be addressed. Tel: +34 918373112; Fax: +34 915360432; Email: srdecordoba{at}cib.csic.es
Received November 4, 2004; Revised December 7, 2004; Accepted January 17, 2005
The efficiency of the complement system as an innate immune defense mechanism depends on a fine control that restricts its action to pathogens and prevents non-specific damage to host tissues. Genetic and functional analyses have shown that this critical control of complement activation may be impaired in atypical hemolytic uremic syndrome (aHUS) patients. Mutations in HF1, MCP or FI have been found in aHUS patients, but incomplete penetrance of the disease in individuals carrying these mutations is relatively frequent and no genetic defect has yet been found in a majority of aHUS patients. We report here the identification of a specific SNP haplotype block, spanning the MCP gene in the regulators of complement activation gene cluster, which is over-represented in aHUS patients and strongly associates with the severity of the disease. Linkage disequilibrium analyses suggest that this SNP haplotype also includes the CR1, DAF and C4BP genes. Initial studies identified two SNPs in the haplotype that influence the transcription activity of the MCP promoter in transient transfection experiments. Notably, the SNP haplotype block was found to be particularly frequent among patients who carry mutations in HF1, MCP or FI. These findings and the identification of aHUS patients carrying mutations in two complement regulatory genes provide an important insight into the etiology of aHUS. Together, they suggest that complement regulatory molecules act as a protein network and that multiple hits, involving plasma- and membrane-associated complement regulatory proteins, are necessary to impair protection to host tissues and to confer significant predisposition to aHUS.
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