Novel factor H mutation associated with familial membranoproliferative glomerulonephritis type I

Idiopathic membranoproliferative glomerulonephritis (MPGN) is a rare disease, accounting for 3-5% of all cases of primary nephritic syndrome. We report an uncommon case of familial MPGN type I associated with a new mutation in the complement factor H gene (CFH).

Clinical data were collected on three siblings with known factor H deficiency who presented with MPGN. All underwent immunological and genetic assays. Their parents and ten healthy adults served as controls for the DNA analysis.

All three children presented with recurrent episodes of hematuria and proteinuria, the youngest starting at age 5 months. One child currently has nephrotic syndrome and end-stage renal disease. All of the children were found to be homozygous for a C.262C > A (p.Pro88Thr) mutation in exon 3 of CFH that is associated with a quantitative/functional deficiency of factor H. The parents of the three siblings were found to be heterozygous for the mutation. None of the controls carried this mutation.

Different mutations in CFH may be responsible for different glomerular diseases, including MPGN type I. A modifier gene or an environmental trigger may contribute to this phenotype-genotype discrepancy. Understanding the role of the alternative complement pathway in this disease would allow us to offer these patients more targeted therapy, including a clinical trial of eculizumab.