| Literature DB >> 25581430 |
Michael Y Zhang1, Jane E Churpek2, Siobán B Keel3, Tom Walsh4, Ming K Lee4, Keith R Loeb5, Suleyman Gulsuner4, Colin C Pritchard6, Marilyn Sanchez-Bonilla1, Jeffrey J Delrow7, Ryan S Basom7, Melissa Forouhar8, Boglarka Gyurkocza1, Bradford S Schwartz9, Barbara Neistadt2, Rafael Marquez2, Christopher J Mariani2, Scott A Coats1, Inga Hofmann10, R Coleman Lindsley11, David A Williams10, Janis L Abkowitz3, Marshall S Horwitz12, Mary-Claire King4, Lucy A Godley2, Akiko Shimamura13.
Abstract
We report germline missense mutations in ETV6 segregating with the dominant transmission of thrombocytopenia and hematologic malignancy in three unrelated kindreds, defining a new hereditary syndrome featuring thrombocytopenia with susceptibility to diverse hematologic neoplasms. Two variants, p.Arg369Gln and p.Arg399Cys, reside in the highly conserved ETS DNA-binding domain. The third variant, p.Pro214Leu, lies within the internal linker domain, which regulates DNA binding. These three amino acid sites correspond to hotspots for recurrent somatic mutation in malignancies. Functional studies show that the mutations abrogate DNA binding, alter subcellular localization, decrease transcriptional repression in a dominant-negative fashion and impair hematopoiesis. These familial genetic studies identify a central role for ETV6 in hematopoiesis and malignant transformation. The identification of germline predisposition to cytopenias and cancer informs the diagnosis and medical management of at-risk individuals.Entities:
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Year: 2015 PMID： 25581430 PMCID： PMC4540357 DOI： 10.1038/ng.3177
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330