title: Variant-specific quantification of factor H in plasma identifies null alleles associated with atypical hemolytic uremic syndrome.
abstract: Atypical hemolytic uremic syndrome (aHUS) is associated with complement alternative pathway defects in over half the cases. Point mutations that affect complement surface regulation are common in factor H (CFH); however, sometimes individuals have null mutations in heterozygosis. The latter are difficult to identify, although a consistently low plasma factor H (fH) concentration is suggestive; definitive proof requires demonstration that the mutant sequence is not expressed in vitro. Here, novel reagents and assays that distinguish and individually quantify the common factor H-Y402H polymorphic variants were used to identify alleles of the CFH gene, resulting in low or null expression of full-length fH and also normal or increased expression of the alternative splice product factor H-like-1 (FHL-1). Our assay identified three Y402H heterozygotes with low or absent fH-H402 but normal or increased FHL-1-H402 levels in a cohort of affected patients. Novel mutations explained the null phenotype in two cases, which was confirmed by family studies in one. In the third case, family studies showed that a known mutation was present on the Y allele. The cause of reduced expression of the H allele was not found, although the data suggested altered splicing. In each family, inheritance of low expression or null alleles for fH strongly associated with aHUS. Thus, our assays provide a rapid means to identify fH expression defects without resorting to gene sequencing or expression analysis.
authors: Department of Infection, School of Medicine, Cardiff University, Cardiff, UK.
authors: Svetlana
authors: S
authors: Hakobyan
authors: Agustín
authors: A
authors: Tortajada
authors: Claire L
authors: CL
authors: Harris
authors: Santiago R
authors: SR
authors: de Córdoba
authors: Bryan P
authors: BP
authors: Morgan
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D017242:Complement Factor H / Q000032:analysis* / Q000172:deficiency / Q000235:genetics*; D005190:Family; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D005838:Genotype; D006463:Hemolytic-Uremic Syndrome / Q000235:genetics*; D006801:Humans; D007202:Indicators and Reagents; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic
chemical_list: D007202:Indicators and Reagents; D017242:Complement Factor H