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Mutations in CD46, a complement regulatory protein, predispose to atypical HUS
Timothy H J Goodship1, M Kathryn Liszewski, Elizabeth J Kemp
1Institute of Human Genetics, University of Newcastle upon Tyne, NE 13BZ, UK. t.h.j.goodship@ncl.ac.uk
Trends in Molecular Medicine
|May 4, 2004
Summary
Mutations in Membrane Cofactor Protein (MCP, CD46) are linked to atypical hemolytic uremic syndrome (HUS). These genetic changes impair MCP
Area of Science:
- Immunology
- Genetics
- Nephrology
Background:
- Membrane cofactor protein (MCP, CD46) is a key regulator of the complement system, inhibiting complement activation by inactivating C3b.
- Factor H mutations are implicated in 15-30% of atypical hemolytic uremic syndrome (HUS) cases.
Purpose of the Study:
- To investigate the role of mutations in the MCP gene in the development of atypical hemolytic uremic syndrome (HUS).
Main Methods:
- Genetic analysis of four families with suspected HUS.
- Characterization of identified MCP gene mutations, including deletions and substitutions.
- Assessment of mutant MCP protein expression and function.
Main Results:
- Four families with MCP gene mutations were identified.
- Mutations included heterozygous deletions causing intracellular retention or premature stop codons, and a substitution (S206P) leading to impaired C3b inactivation.
- These mutations resulted in dysfunctional MCP, contributing to complement dysregulation.
Conclusions:
- Genetic defects in Membrane Cofactor Protein (MCP, CD46) are associated with atypical hemolytic uremic syndrome (HUS).
- These findings highlight the critical role of complement regulation in preventing HUS and suggest MCP as a potential therapeutic target.