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Title: Complement abnormalities in membranoproliferative glomerulonephritis and C3 glomerulopathy
Authors: Wong, Edwin Kwan Soon
Issue Date: 2016
Publisher: Newcastle University
Abstract: Membranoproliferative glomerulonephritis (MPGN) and C3 glomerulopathy (C3G) are rare diseases that associate with dysregulation of the alternative pathway (AP). The earliest abnormalities associated with these diseases were C3 nephritic factor and also rare genetic variants in the gene CFH that caused factor H (FH) deficiency. Since then, other acquired and genetic abnormalities in AP have been reported in MPGN and C3G. The aim of this project was to screen cohorts of MPGN and C3G for such abnormalities. Screening for rare sequence variants in genes encoding proteins involved in AP activity in two cohorts revealed a low prevalence of genetic abnormalities. Compared to the prevalence of C3 nephritic factor and autoantibodies to complement proteins, it was clear that the predominant abnormalities in these cohorts were acquired. Though few, rare genetic variants identified in CFH were studied in functional studies. The first was identified in a case of familial MPGN in the N-terminal domain of CFH. Functional studies included surface plasmon resonance and haemolytic assays to study a mutant protein in the setting of a short fragment comprising the N-terminal domain of FH. This initial study confirmed loss of function in a familial variant and formed the basis for further studies. In studies of eight other variants identified in MPGN and C3G and two other diseases that share complement risk factors, only two variants were likely to be functionally significant as demonstrated by complete loss of function. This highlights the need for such studies to correctly identify important variants. The significant functional effects initially identified in studies using short fragments were then confirmed in studies using full length protein. The significance of rare genetic variants in CFH needs to be considered even though MPGN and C3G are largely an autoimmune phenomenon.
Description: PhD Thesis
Appears in Collections:Institute of Genetic Medicine

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