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Lookup NU author(s): Dr Veronique Fremaux-Bacchi, Professor Tim Goodship
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Atypical hemolytic uremic syndrome (aHUS) is a disease of hemolytic anemia, thrombocytopenia, and renal failure associated with defective alternative pathway (AP) complement control. Previously, we presented a database (www.FH-HUS.org) focusing on aHUS mutations in the Factor H gene (CFH). Here, new aHUS mutations are reported for the complement regulatory proteins Factor H (FH), Factor I (FI), and membrane cofactor protein (MCP). Additional mutations or polymorphisms within CFH have been associated with membranoproliferative glomerulonephritis (MPGN) and age-related macular degeneration (AMD). Accordingly, the database now includes substitutions that predispose to aHUS, MPGN, and AMD. For this, structural models for the domains in MCP and FI were developed using homology modeling. With this new database, patients with mutations in more than one gene can be displayed and interpreted in a coherent manner. The database also includes SNP polymorphisms in CFH, MCP, and IF. There are now a total of 167 genetic alterations, including 100 in CFH, 43 in MCP, and 24 in IF. The mutations characterize clinical outcomes that vary from several AMD-associated polymorphisms to those associated with aHUS, MPGN, or FI deficiency. A consensus short complement regulator (SCR) domain structure facilitated the interpretations of aHUS mutations. Specific locations within this consensus domain often correlate with the occurrence of clinical phenotypes. The AMD Tyr402His polymorphism is structurally located at a hotspot for several aHUS mutations. The database emphasizes the causative role of the alternative pathway of complement in disease and provides a repository of knowledge to assist future diagnosis and novel therapeutic approaches. © 2006 Wiley-Liss, Inc.
Author(s): Saunders RE, Abarrategui-Garrido C, Fremeaux-Bacchi V, Goicoechea De Jorge E, Goodship THJ, Lopez Trascasa M, Noris M, Ponce Castro IM, Remuzzi G, Rodriguez De Cordoba S, Sanchez-Corral P, Skerka C, Zipfel PF, Perkins SJ
Publication type: Article
Publication status: Published
Journal: Human Mutation
Year: 2007
Volume: 28
Issue: 3
Pages: 222-234
ISSN (print): 1059-7794
ISSN (electronic): 1098-1004
Publisher: John Wiley & Sons, Inc.
URL: http://dx.doi.org/10.1002/humu.20435
DOI: 10.1002/humu.20435
PubMed id: 17089378
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