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Nat Genet. 2015 May;47(5):535-538. doi: 10.1038/ng.3253. Epub 2015 Mar 25.

Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.

Author information

1
Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, CO, USA.
2
Human Medical Genetics and Genomics Program, University of Colorado AMC, Aurora, Colorado, USA.
3
Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
5
Children's Hospital of Michigan, Wayne State University, Detroit, MI, USA.
6
Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy.
7
Department of Medical Sciences, University of Trieste, Trieste, Italy.
8
Institute for Maternal and Child Health- IRCCS Burlo Garofolo, Trieste, Italy.
9
Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, Colorado, USA.
10
Department of Internal Medicine, Haematology/Oncology, University Hospital Brno, CZ.
11
Department of Medicine, University of Toronto, Division of Rheumatology University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
12
Instituto de Investigaciones Medicas Alfredo Lanari, Universidad de Buenos Aires, Buenos Aires, Argentina.
13
Departments of Medicine, University of Colorado, AMC, Aurora, Colorado, USA.
14
Department of Pathology, University of Colorado, AMC, Aurora, Colorado, USA.
15
Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.
16
Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA.
17
Department of Paediatrics, Division of Haematology/Oncology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.
#
Contributed equally

Abstract

Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia. We identified a family with autosomal dominant thrombocytopenia, high erythrocyte mean corpuscular volume (MCV) and two occurrences of B cell-precursor acute lymphoblastic leukemia (ALL). Whole-exome sequencing identified a heterozygous single-nucleotide change in ETV6 (ets variant 6), c.641C>T, encoding a p.Pro214Leu substitution in the central domain, segregating with thrombocytopenia and elevated MCV. A screen of 23 families with similar phenotypes identified 2 with ETV6 mutations. One family also had a mutation encoding p.Pro214Leu and one individual with ALL. The other family had a c.1252A>G transition producing a p.Arg418Gly substitution in the DNA-binding domain, with alternative splicing and exon skipping. Functional characterization of these mutations showed aberrant cellular localization of mutant and endogenous ETV6, decreased transcriptional repression and altered megakaryocyte maturation. Our findings underscore a key role for ETV6 in platelet formation and leukemia predisposition.

PMID:
25807284
PMCID:
PMC4631613
DOI:
10.1038/ng.3253
[Indexed for MEDLINE]
Free PMC Article

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