Genetic analysis and functional characterization of novel mutations in a series of patients with atypical hemolytic uremic syndrome
2016; Elsevier BV; Volume: 71; Linguagem: Inglês
10.1016/j.molimm.2016.01.003
ISSN1872-9142
AutoresNóra Szarvas, Ágnes Szilágyi, Dorottya Csuka, Beáta Takács, Krisztina Rusai, Thomas Müller, Klaus Arbeiter, Marienn Réti, Agnès Haris, László Wagner, Szilárd Török, Kata Kelen, Attila J. Szabó, György Reusz, B. Paul Morgan, Zoltán Prohászka,
Tópico(s)Renal Diseases and Glomerulopathies
ResumoAtypical 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.
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