Characterization of a factor H mutation that perturbs the alternative pathway of complement in a family with membranoproliferative GN.
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.
Institutes of Genetic Medicine, and.
Edwin K S
EK
Wong
Institutes of Genetic Medicine, and.
Holly E
HE
Anderson
Edinburgh Biomolecular Nuclear Magnetic Resonance Unit, and.
Andrew P
AP
Herbert
Institutes of Genetic Medicine, and.
Rachel C
RC
Challis
The Renal Unit, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; and.
Paul
P
Brown
Institutes of Genetic Medicine, and.
Geisilaine S
GS
Reis
Institutes of Genetic Medicine, and.
James O
JO
Tellez
Institutes of Genetic Medicine, and.
Lisa
L
Strain
The Renal Unit, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; and.
Nicholas
N
Fluck
The Renal Unit, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; and.
Ann
A
Humphrey
The Renal Unit, Aberdeen Royal Infirmary, Aberdeen, United Kingdom; and.
Alison
A
Macleod
Medical Research Council Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom;
Anna
A
Richards
Institutes of Genetic Medicine, and.
Daniel
D
Ahlert
Institutes of Genetic Medicine, and.
Mauro
M
Santibanez-Koref
Edinburgh Biomolecular Nuclear Magnetic Resonance Unit, and.
Paul N
PN
Barlow
Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom;
Kevin J
KJ
Marchbank
Cardiff Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom.
Claire L
CL
Harris
Institutes of Genetic Medicine, and.
Timothy H J
TH
Goodship
Institutes of Genetic Medicine, and david.kavanagh@ncl.ac.uk.
David
D
Kavanagh
D000818:Animals; D017242:Complement Factor H / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D003170:Complement Pathway, Alternative / Q000235:genetics* / Q000276:immunology; D018360:Crystallography, X-Ray; D004912:Erythrocytes / Q000166:cytology / Q000276:immunology*; D005192:Family Health; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000235:genetics* / Q000276:immunology*; D006239:Haplotypes; D000081208:Hereditary Complement Deficiency Diseases; D006579:Heterozygote; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000276:immunology; D008297:Male; D010375:Pedigree; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D012756:Sheep; D013329:Structure-Activity Relationship
D017242:Complement Factor H
complement; immunology; membranoproliferative GN (MPGN)