TY - JOUR T1 - Mutations in the 5' UTR of ANKRD26, the ankirin repeat domain 26 gene, cause an autosomal-dominant form of inherited thrombocytopenia, THC2. JF - Am J Hum Genet Y1 - 2011 A1 - Pippucci, Tommaso A1 - Savoia, Anna A1 - Perrotta, Silverio A1 - Pujol-Moix, Núria A1 - Noris, Patrizia A1 - Castegnaro, Giovanni A1 - Pecci, Alessandro A1 - Gnan, Chiara A1 - Punzo, Francesca A1 - Marconi, Caterina A1 - Gherardi, Samuele A1 - Loffredo, Giuseppe A1 - De Rocco, Daniela A1 - Scianguetta, Saverio A1 - Barozzi, Serena A1 - Magini, Pamela A1 - Bozzi, Valeria A1 - Dezzani, Luca A1 - Di Stazio, Mariateresa A1 - Ferraro, Marcella A1 - Perini, Giovanni A1 - Seri, Marco A1 - Balduini, Carlo L KW - Ankyrin Repeat KW - Base Sequence KW - Chromosome Breakage KW - Chromosome Disorders KW - Conserved Sequence KW - Female KW - Genes, Dominant KW - Genetic Loci KW - Haploinsufficiency KW - Humans KW - Male KW - Molecular Sequence Data KW - Mutation KW - Pedigree KW - Thrombocytopenia AB -

THC2, an autosomal-dominant thrombocytopenia described so far in only two families, has been ascribed to mutations in MASTL or ACBD5. Here, we show that ANKRD26, another gene within the THC2 locus, and neither MASTL nor ACBD5, is mutated in eight unrelated families. ANKRD26 was also found to be mutated in the family previously reported to have an ACBD5 mutation. We identified six different ANKRD26 mutations, which were clustered in a highly conserved 19 bp sequence located in the 5' untranslated region. Mutations were not detected in 500 controls and are absent from the 1000 Genomes database. Available data from an animal model and Dr. Watson's genome give evidence against haploinsufficiency as the pathogenetic mechanism for ANKRD26-mediated thrombocytopenia. The luciferase reporter assay suggests that these 5' UTR mutations might enhance ANKRD26 expression. ANKRD26 is the ancestor of a family of primate-specific genes termed POTE, which have been recently identified as a family of proapoptotic proteins. Dysregulation of apoptosis might therefore be the pathogenetic mechanism, as demonstrated for another thrombocytopenia, THC4. Further investigation is needed to provide evidence supporting this hypothesis.

VL - 88 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21211618?dopt=Abstract ER -