Mutations in CD46, a complement regulatory protein, predispose to atypical HUS.
Membrane cofactor protein (MCP, CD46) is a widely expressed transmembrane complement regulator. As does the soluble regulator factor H, it inhibits complement activation by inactivating the C3b that is deposited on target membranes. Factor H mutations have been described in 15-30% of patients with atypical haemolytic uraemic syndrome (HUS). Recent studies have identified mutations in the MCP gene in four families. In one, a heterozygous deletion resulted in the intracellular retention of the mutant protein. In another, a different heterozygous deletion led to a premature stop codon and the loss of the C-terminus. In the other two, a substitution (S206P) resulted in cell-surface expression but inefficient inactivation of surface-bound C3b. These findings provide further evidence that complement dysregulation predisposes to the development of HUS.
Goodship
Timothy H J
TH
Institute of Human Genetics, University of Newcastle upon Tyne, NE 13BZ, UK. t.h.j.goodship@ncl.ac.uk
Liszewski
M Kathryn
MK
Kemp
Elizabeth J
EJ
Richards
Anna
A
Atkinson
John P
JP
D002462:Cell Membrane / Q000276:immunology*; D018389:Codon, Nonsense; D003167:Complement Activation / Q000235:genetics; D003179:Complement C3b / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics* / Q000276:immunology; D006579:Heterozygote; D006801:Humans; D051916:Membrane Cofactor Protein / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D012307:Risk Factors; D017384:Sequence Deletion
C497857:CD46 protein, human; C493495:CFH protein, human; D018389:Codon, Nonsense; D051916:Membrane Cofactor Protein; D003179:Complement C3b; D017242:Complement Factor H