title: Genetic deficiency of complement factor H in a patient with age-related macular degeneration and membranoproliferative glomerulonephritis.
abstract: Age-related macular degeneration (AMD) and membranoproliferative glomerulonephritis type II (MPGN2) are dense deposit diseases that share a genetic association with complement genes and have complement proteins as important components of the dense deposits. Here, we present the case of a 64-year-old smoker male who developed both AMD and MPGN2 in his late 50s. The patient presented persistent low plasma levels of C3, factor H levels in the lower part of the normal range and C3NeF traces. Genetic analyses of the CFH, CFB, C3, CFHR1-CFHR3 and LOC387715/HTRA1 genes revealed that the patient was heterozygote for a novel missense mutation in exon 9 of CFH (c.1292 G>A) that results in a Cys431Tyr substitution in SCR7 of the factor H protein. In addition, he was homozygote for the His402 CFH allele, heterozygote for the Ser69 LOC387715 allele, homozygote for the Arg32 (BFS) CFB allele, heterozygote for the Gly102 (C3F) C3 allele and carried no deletion of the CFHR1/CFHR3 genes. Proteomic and functional analyses indicate absence in plasma of the factor H allele carrying the Cys431Tyr mutation. As a whole, these data recapitulate a prototypical complement genetic profile, including a partial factor H deficiency and the presence of major risk factors for AMD and MPGN2, which support the hypothesis that these dense deposit diseases have a common pathogenic mechanism involving dysregulation of the alternative pathway of complement activation.
authors.affiliation: Centro de Investigaciones Biológicas and Centro de Investigación Biomédica en Enfermedades Raras, Ramiro de Maeztu 9, Madrid, Spain.
authors.forename: Tamara
authors.initials: T
authors.lastname: Montes
authors.forename: Elena
authors.initials: E
authors.lastname: Goicoechea de Jorge
authors.forename: Rosa
authors.initials: R
authors.lastname: Ramos
authors.forename: Montserrat
authors.initials: M
authors.lastname: Gomà
authors.forename: Octavi
authors.initials: O
authors.lastname: Pujol
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Corral
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez de Córdoba
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D017242:Complement Factor H / Q000737:chemistry / Q000235:genetics*; D003545:Cysteine; D005123:Eye / Q000473:pathology; D020022:Genetic Predisposition to Disease; D015432:Glomerulonephritis, Membranoproliferative / Q000150:complications* / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000473:pathology; D008268:Macular Degeneration / Q000150:complications* / Q000235:genetics*; D013058:Mass Spectrometry; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011994:Recombinant Proteins; D014443:Tyrosine
chemical_list: D011994:Recombinant Proteins; D014443:Tyrosine; D017242:Complement Factor H; D003545:Cysteine