title: Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome.
abstract: Atypical hemolytic uremic syndrome (aHUS) is a rare disorder caused by dysregulation of the complement alternative pathway, and associated with mutations in genes of complement components and regulators. In the recent years several studies have been published describing these mutations, however, no data is available from the Central and Eastern European region. In this study we present a detailed genetic analysis of our 30 patients, hospitalized with the diagnosis of aHUS in the past 7 years. We analyzed the genetic variants of genes CFH, CFI, CD46, THBD, CFB and C3; furthermore the possible effect of mutations that may alter the function or level of factor H protein was also investigated. We identified 27 (12 novel and 15 previously described) potentially disease-causing mutations in the candidate genes in 23 patients. Genetic analysis of family members revealed that in most cases the disease develops in individuals with multiple genetic risk factors, which may explain the low penetrance of the mutations. Here we showed that two novel mutations (p.W198R, p.P1161T) and a previously reported one (p.R1215Q) in CFH caused impaired regulation as indicated by increased lysis in hemolytic test, while four CFH mutations (p.V609D, p.S722X, p.T1216del and p.C448Y) were associated with decreased factor H protein level in serum as determined by allele-specific immunoassay. These results further point to the necessity of complete genetic workup of patients with aHUS and to the importance of functional characterization of novel variations.
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Nóra
authors.initials: N
authors.lastname: Szarvas
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Szilágyi
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Dorottya
authors.initials: D
authors.lastname: Csuka
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Takács
authors.affiliation: Department of Pediatrics, Medical University Vienna, Austria.
authors.forename: Krisztina
authors.initials: K
authors.lastname: Rusai
authors.affiliation: Department of Pediatrics, Medical University Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Müller
authors.affiliation: Department of Pediatrics, Medical University Vienna, Austria.
authors.forename: Klaus
authors.initials: K
authors.lastname: Arbeiter
authors.affiliation: Department of Hematology and Stem Cell Transplantation, St. István and St. László Hospital, Budapest, Hungary.
authors.forename: Marienn
authors.initials: M
authors.lastname: Réti
authors.affiliation: Department of Nephrology, St. Margit Hospital, Budapest, Hungary.
authors.forename: Ágnes
authors.initials: Á
authors.lastname: Haris
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Wagner
authors.affiliation: Department of Transplantation and Surgery, Semmelweis University, Budapest, Hungary.
authors.forename: Szilárd
authors.initials: S
authors.lastname: Török
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Kata
authors.initials: K
authors.lastname: Kelen
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Attila J
authors.initials: AJ
authors.lastname: Szabó
authors.affiliation: 1st Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: György S
authors.initials: GS
authors.lastname: Reusz
authors.affiliation: Complement Biology Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. Electronic address: prohaszka.zoltan@med.semmelweis-univ.hu.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Prohászka
mesh_terms: D000293:Adolescent; D000328:Adult; D065766:Atypical Hemolytic Uremic Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003176:Complement C3 / Q000235:genetics; D011415:Complement Factor B / Q000235:genetics; D017242:Complement Factor H / Q000235:genetics*; D017244:Complement Factor I / Q000235:genetics; D004252:DNA Mutational Analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D055815:Young Adult
chemical_list: D003176:Complement C3; D017242:Complement Factor H; D017244:Complement Factor I; D011415:Complement Factor B
keywords: Atypical hemolytic uremic syndrome; CFH; Complement; Mutation; Y402H