Complement factor H deficiency and endocapillary glomerulonephritis due to paternal isodisomy and a novel factor H mutation

Abstract

Complement factor H (CFH) is a regulator of the alternative complement activation pathway. Mutations in the CFH gene are associated with atypical hemolytic uremic syndrome, membranoproliferative glomerulonephritis type II and C3 glomerulonephritis. Here, we report a 6-month-old CFH-deficient child presenting with endocapillary glomerulonephritis rather than membranoproliferative glomerulonephritis (MPGN) or C3 glomerulonephritis. Sequence analyses showed homozygosity for a novel CFH missense mutation (Pro139Ser) associated with severely decreased CFH plasma concentration (o6%) but normal mRNA splicing and expression. The father was heterozygous carrier of the mutation, but the mother was a non-carrier. Thus, a large deletion in the maternal CFH locus or uniparental isodisomy was suspected. Polymorphic markers across chromosome 1 showed homozygosity for the paternal allele in all markers and a lack of the maternal allele in six informative markers. This combined with a comparative genomic hybridization assay demonstrated paternal isodisomy. Uniparental isodisomy increases the risk of homozygous variations in other genes on the affected chromosome. Therefore, we analyzed other susceptibility genes on chromosome 1 and found no sequence variation in membrane cofactor protein, but homozygosity for the common deletion of CFH-related proteins 1 and 3, which may contribute to the early onset of disease.

Familial craniosynostosis associated with a microdeletion involving the NFIA gene

“…Labeling and hybridization were performed according to the protocol provided by Agilent (Protocol v6.0, November 2008) as described in Schejbel et al, 2011. Quantitative PCR was used for the confirmation of array CGH finding in the proband and investigation of parents and siblings [performed as described by Roos et al (2009)]. …”

Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids

“…Multiple variants of CFH have been identified as contributing to the pathogenesis of diseases such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura (32), glomerulonephritis (33), intracerebral hemorrhage (34), lung cancer (35), and sudden sensorineural hearing loss (36). Thus, far, variants of CFH that have been associated directly with AMD risk include Y402H, I62V (37)(38)(39), and R1210C (40).…”

Chemical Chaperones Curcumin and 4-Phenylbutyric Acid Improve Secretion of Mutant Factor H R127H by Fibroblasts from a Factor H-Deficient Patient

“…Complete FH deficiency (homozygous) is rare: only 23 cases in 13 different families have been reported in the literature (8,9 (21). All these mutations are associated with secretion delay of FH.…”