Journal
NATURE GENETICS
Volume 47, Issue 2, Pages 180-185Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.3177
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Funding
- US National Institutes of Health [R24DK093425, R24DK099808-01, K12CA139160]
- Ghiglione Aplastic Anemia Fund
- Julian's Dinosaur Guild from Seattle Children's Hospital
- Medical Scientist Training Program [T32GM007266]
- Genetic Approaches to Aging Training grant [T32AG000057]
- Cancer Research Foundation
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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.
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