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

Rebecca E. Saunders, Cynthia Abarrategui-Garrido, Véronique Frémeaux-Bacchi, Elena Goicoechea De Jorge, Timothy H J Goodship, Margarita López Trascasa, Marina Noris, Isabel Maria Ponce Castro, Giuseppe Remuzzi, Santiago Rodríguez De Córdoba, Pilar Sánchez-Corral, Christine Skerka, Peter F. Zipfel, Stephen J. Perkins

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)222-234
Number of pages13
JournalHuman Mutation
Volume28
Issue number3
DOIs
Publication statusPublished - Mar 2007

Fingerprint

CD46 Antigens
Complement Factor H
Structural Models
Databases
Macular Degeneration
Mutation
Membranoproliferative Glomerulonephritis
Alternative Complement Pathway
Hemolytic Anemia
Atypical Hemolytic Uremic Syndrome
Thrombocytopenia
Genes
Renal Insufficiency
Single Nucleotide Polymorphism
Complement System Proteins
Phenotype

Keywords

  • CFH
  • Complement
  • Factor H
  • Factor I
  • Hemolytic uremic syndrome
  • IF
  • Immunodeficiency diseases
  • MCP
  • Membrane cofactor protein
  • Mutation database

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Saunders, R. E., Abarrategui-Garrido, C., Frémeaux-Bacchi, V., Goicoechea De Jorge, E., Goodship, T. H. J., López Trascasa, M., ... Perkins, S. J. (2007). 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. Human Mutation, 28(3), 222-234. https://doi.org/10.1002/humu.20435

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. / Saunders, Rebecca E.; Abarrategui-Garrido, Cynthia; Frémeaux-Bacchi, Véronique; Goicoechea De Jorge, Elena; Goodship, Timothy H J; López Trascasa, Margarita; Noris, Marina; Ponce Castro, Isabel Maria; Remuzzi, Giuseppe; Rodríguez De Córdoba, Santiago; Sánchez-Corral, Pilar; Skerka, Christine; Zipfel, Peter F.; Perkins, Stephen J.

In: Human Mutation, Vol. 28, No. 3, 03.2007, p. 222-234.

Research output: Contribution to journalArticle

Saunders, RE, Abarrategui-Garrido, C, Frémeaux-Bacchi, V, Goicoechea De Jorge, E, Goodship, THJ, López Trascasa, M, Noris, M, Ponce Castro, IM, Remuzzi, G, Rodríguez De Córdoba, S, Sánchez-Corral, P, Skerka, C, Zipfel, PF & Perkins, SJ 2007, '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', Human Mutation, vol. 28, no. 3, pp. 222-234. https://doi.org/10.1002/humu.20435
Saunders, Rebecca E. ; Abarrategui-Garrido, Cynthia ; Frémeaux-Bacchi, Véronique ; Goicoechea De Jorge, Elena ; Goodship, Timothy H J ; López Trascasa, Margarita ; Noris, Marina ; Ponce Castro, Isabel Maria ; Remuzzi, Giuseppe ; Rodríguez De Córdoba, Santiago ; Sánchez-Corral, Pilar ; Skerka, Christine ; Zipfel, Peter F. ; Perkins, Stephen J. / 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. In: Human Mutation. 2007 ; Vol. 28, No. 3. pp. 222-234.
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