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Characterization of a Factor H Mutation That Perturbs the Alternative Pathway of Complement in a Family with Membranoproliferative GN

Lookup NU author(s): Dr Edwin Wong, Dr Holly Anderson, Rachel Challis, Dr Lisa Turnbull, Gladys -, Dr Mauro Santibanez Koref, Professor Kevin MarchbankORCiD, Professor Claire Harris, Professor Tim Goodship, Professor David KavanaghORCiD


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Complement C3 activation is a characteristic finding in membranoproliferative GN (MPGN). This activation can be caused by immune complex deposition or an acquired or inherited defect in complement regulation. Deficiency of complement factor H has long been associated with MPGN. More recently, heterozygous genetic variants have been reported in sporadic cases of MPGN, although their functional significance has not been assessed. We describe a family with MPGN and acquired partial lipodystrophy. Although C3 nephritic factor was shown in family members with acquired partial lipodystrophy, it did not segregate with the renal phenotype. Genetic analysis revealed a novel heterozygous mutation in complement factor H (R83S) in addition to known risk polymorphisms carried by individuals with MPGN. Patients with MPGN had normal levels of factor H, and structural analysis of the mutant revealed only subtle alterations. However, functional analysis revealed profoundly reduced C3b binding, cofactor activity, and decay accelerating activity leading to loss of regulation of the alternative pathway. In summary, this family showed a confluence of common and rare functionally significant genetic risk factors causing disease. Data from our analysis of these factors highlight the role of the alternative pathway of complement in MPGN.

Publication metadata

Author(s): Wong EKS, Anderson HE, Herbert AP, Challis RC, Brown P, Reis GS, Tellez JO, Strain L, Fluck N, Humphrey A, Macleod A, Richards A, Ahlert D, Santibanez-Koref M, Barlow PN, Marchbank KJ, Harris CL, Goodship THJ, Kavanagh D

Publication type: Article

Publication status: Published

Journal: Journal of American Society of Nephrology

Year: 2014

Volume: 25

Issue: 11

Pages: 2425-2433

Print publication date: 01/11/2014

Online publication date: 10/04/2014

Acceptance date: 08/03/2014

ISSN (print): 1046-6673

ISSN (electronic): 1533-3450

Publisher: American Society of Nephrology


DOI: 10.1681/ASN.2013070732


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Funder referenceFunder name
Instituto Nacional de Ciencia e Tecnologia de Medicina Molecular-Universidade Federal de Minas Gerais
Rosetrees Trust
Wellcome Trust
305608European Union
RP29/2010Kidney Research UK
095884/Z/11/ZWellcome Trust