title: 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 (<6%) 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.
authors.affiliation: Department of Clinical Immunology, Laboratory of Molecular Medicine, Rigshospitalet, Copenhagen, Denmark. l.schejbel@gmail.com
authors.forename: L
authors.initials: L
authors.lastname: Schejbel
authors.forename: I M
authors.initials: IM
authors.lastname: Schmidt
authors.forename: M
authors.initials: M
authors.lastname: Kirchhoff
authors.forename: C B
authors.initials: CB
authors.lastname: Andersen
authors.forename: H V
authors.initials: HV
authors.lastname: Marquart
authors.forename: P
authors.initials: P
authors.lastname: Zipfel
authors.forename: P
authors.initials: P
authors.lastname: Garred
mesh_terms: D000483:Alleles; D001798:Blood Proteins / Q000235:genetics; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D003180:Complement C3b Inactivator Proteins / Q000235:genetics; D017242:Complement Factor H / Q000172:deficiency* / Q000235:genetics*; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000276:immunology; D020125:Mutation, Missense; D012333:RNA, Messenger / Q000235:genetics; D017422:Sequence Analysis, DNA; D024182:Uniparental Disomy / Q000235:genetics*
chemical_list: D001798:Blood Proteins; C517621:CFHR1 protein, human; C105970:CFHR3 protein, human; D003180:Complement C3b Inactivator Proteins; D051916:Membrane Cofactor Protein; D012333:RNA, Messenger; D017242:Complement Factor H