Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia

摘要: Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome, characterized by and congenital fusion of the radius ulna. A heterozygous HOXA11 mutation has been identified in two unrelated families as a cause RUSAT. However, mutations are absent number individuals RUSAT, which suggests that other genetic loci contribute to In current study, we performed whole exome sequencing individual RUSAT her healthy parents de novo missense MECOM, encoding EVI1, Subsequent analysis MECOM revealed additional mutations. These three were clustered within 8th zinc finger motif C-terminal domain EVI1. Chromatin immunoprecipitation qPCR assays regions harboring ETS-like known EVI1 binding site showed reduction immunoprecipitated DNA for two EVI1 mutants compared wild-type Furthermore, reporter led alterations both AP-1- TGF-β-mediated transcriptional responses. functional suggest dysregulation mutant could be associated development We report resulting Mendelian disorder provide compelling evidence critical role normal hematopoiesis forelimbs fingers humans.