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Lookup NU author(s): Professor David KavanaghORCiD, Dr Lisa Turnbull, Professor Kevin MarchbankORCiD, Professor Claire Harris, Professor Tim Goodship
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Genomic disorders affecting the genes encoding factor H (fH) and the 5 factor H related proteins have been described in association with atypical hemolytic uremic syndrome. These include deletions of CFHR3, CFHR1, and CFHR4 in association with fH autoantibodies and the formation of a hybrid CFH/CFHR1 gene. These occur through nonallelic homologous recombination secondary to the presence of large segmental duplications (macrohomology) in this region. Using multiplex ligation-dependent probe amplification to screen for such genomic disorders, we have identified a large atypical hemolytic uremic syndrome family where a deletion has occurred through microhomology mediated end joining rather than nonallelic homologous recombination. In the 3 affected persons of this family, we have shown that the deletion results in formation of a CFH/CFHR3 gene. We have shown that the protein product of this is a 24 SCR protein that is secreted with nor-mal fluid-phase activity but marked loss of complement regulation at cell surfaces despite increased heparin binding. In this study, we have therefore shown that microhomology in this area of chromosome 1 predisposes to disease associated genomic disorders and that the complement regulatory function of fH at the cell surface is critically dependent on the structural integrity of the whole molecule. (Blood. 2012; 119(2): 591-601)
Author(s): Francis NJ, McNicholas B, Awan A, Waldron M, Reddan D, Sadlier D, Kavanagh D, Strain L, Marchbank KJ, Harris CL, Goodship THJ
Publication type: Article
Publication status: Published
Journal: Blood
Year: 2012
Volume: 119
Issue: 2
Pages: 591-601
Print publication date: 12/01/2012
Date deposited: 30/01/2015
ISSN (print): 0006-4971
ISSN (electronic): 1528-0020
Publisher: American Society of Hematology
URL: http://dx.doi.org/10.1182/blood-2011-03-339903
DOI: 10.1182/blood-2011-03-339903
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