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Title

The interactive Factor H - aHUS mutation database and website: Update and integration of MCP and FI mutations with structural models

AuthorsSaunders, Rebecca E.; Goicoechea de Jorge, Elena ; Rodríguez de Córdoba, Santiago ; Perkins, Stephen
KeywordsFactor H
CFH
Hemolytic uremic syndrome
Factor I
IF
Membrane cofactor protein
MCP
Complement
Mutation database
Immunodeficiency diseases
Issue DateMar-2007
PublisherWiley-Blackwell
CitationHuman Mutation 28(3)222-234(2007)
AbstractAtypical 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
Description13 p.-5 fig.-1 tab.Saunders, Rebecca E. et al.
Publisher version (URL)http://dx.doi.org/10.1002/humu.20435
URIhttp://hdl.handle.net/10261/69363
DOI10.1002/humu.20435
ISSN1059-7794
E-ISSN1098-1004
Appears in Collections:(CIB) Artículos
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