title: The interactive Factor H-atypical hemolytic uremic syndrome mutation database and website: update and integration of membrane cofactor protein and Factor I mutations with structural models.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Royal Free and University College Medical School, University College London, London, United Kingdom.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Saunders
authors.forename: Cynthia
authors.initials: C
authors.lastname: Abarrategui-Garrido
authors.forename: Véronique
authors.initials: V
authors.lastname: Frémeaux-Bacchi
authors.forename: Elena
authors.initials: E
authors.lastname: Goicoechea de Jorge
authors.forename: Timothy H J
authors.initials: TH
authors.lastname: Goodship
authors.forename: Margarita
authors.initials: M
authors.lastname: López Trascasa
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Isabel Maria
authors.initials: IM
authors.lastname: Ponce Castro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: Christine
authors.initials: C
authors.lastname: Skerka
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Perkins
mesh_terms: D000595:Amino Acid Sequence; D017242:Complement Factor H / Q000235:genetics*; D030541:Databases, Genetic; D005340:Fibrinogen / Q000235:genetics*; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000235:genetics; D017386:Sequence Homology, Amino Acid
chemical_list: D051916:Membrane Cofactor Protein; D017242:Complement Factor H; D005340:Fibrinogen