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Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome

Lookup NU author(s): Dr Anna Richards, Professor Judith Goodship, Dr Anne Lampe, Professor Tim Goodship

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Abstract

Membrane cofactor protein (MCP; CD46) is a widely expressed transmembrane complement regulator. Like factor H it inhibits complement activation by regulating C3b deposition on targets. Factor H mutations occur in 10-20% of patients with hemolytic uremic syndrome (HUS). We hypothesized that MCP mutations could predispose to HUS, and we sequenced MCP coding exons in affected individuals from 30 families. MCP mutations were detected in affected individuals of three families: a deletion of two amino acids (D237/S238) in family 1 (heterozygous) and a substitution, S206P, in families 2 (heterozygous) and 3 (homozygous). We evaluated protein expression and function in peripheral blood mononuclear cells from these individuals. An individual with the D237/ S238 deletion had reduced MCP levels and ≈50% C3b binding compared with normal controls. Individuals with the S206P change expressed normal quantities of protein, but demonstrated ≈50% reduction in C3b binding in heterozygotes and complete lack of C3b binding in homozygotes. MCP expression and function was evaluated in transfectants reproducing these mutations. The deletion mutant was retained intracellularly. S206P protein was expressed on the cell surface but had a reduced ability to prevent complement activation, consistent with its reduced C3b binding and cofactor activity. This study presents further evidence that complement dysregulation predisposes to development of thrombotic microangiopathy and that screening patients for such defects could provide informed treatment strategies.

Publication metadata

Author(s): Goodship JA; Goodship THJ; Richards A; Lampe AK; Pirson Y; Wen LS; Atkinson JP; Kemp EJ; Liszewski MK; Decorte R; Muslumanoglu MH; Kavukcu S; Filler G

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 2003

Volume: 100

Issue: 22

Pages: 12966-12971

ISSN (print): 0027-8424

ISSN (electronic): 1091-6490

Publisher: National Academy of Sciences

URL: http://dx.doi.org/10.1073/pnas.2135497100

DOI: 10.1073/pnas.2135497100

PubMed id: 14566051

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