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Am J Hum Genet. 2015 Dec 3;97(6):848-54. doi: 10.1016/j.ajhg.2015.10.010. Epub 2015 Nov 12.

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

Author information

1
Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan. Electronic address: tniihori@med.tohoku.ac.jp.
2
Department of Pediatrics, Tohoku University School of Medicine, Sendai 980-8574, Japan; Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai 989-3126, Japan.
3
Department of Pediatrics, Tohoku University School of Medicine, Sendai 980-8574, Japan.
4
Department of Hematology-Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu 183-8561, Japan.
5
Department of Pediatrics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.
6
Department of Hematology and Oncology, Miyagi Children's Hospital, Sendai 989-3126, Japan.
7
Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan.
8
Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan.
9
Department of Medical Genetics, Tohoku University School of Medicine, Sendai 980-8574, Japan; National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Abstract

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

PMID:
26581901
PMCID:
PMC4678429
DOI:
10.1016/j.ajhg.2015.10.010
[Indexed for MEDLINE]
Free PMC Article

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