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Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia
L. Noetzli, RW. Lo, AB. Lee-Sherick, M. Callaghan, P. Noris, A. Savoia, M. Rajpurkar, K. Jones, K. Gowan, CL. Balduini, A. Pecci, C. Gnan, D. De Rocco, M. Doubek, L. Li, L. Lu, R. Leung, C. Landolt-Marticorena, S. Hunger, P. Heller, A....
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
NLK
ProQuest Central
from 2000-01-01 to 1 year ago
Medline Complete (EBSCOhost)
from 1998-06-01 to 2015-11-30
Health & Medicine (ProQuest)
from 2000-01-01 to 1 year ago
Public Health Database (ProQuest)
from 2000-01-01 to 1 year ago
PubMed
25807284
DOI
10.1038/ng.3253
Knihovny.cz E-resources
- MeSH
- Erythrocytes, Abnormal MeSH
- Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics MeSH
- Adult MeSH
- Exome MeSH
- Genetic Predisposition to Disease MeSH
- Genetic Association Studies MeSH
- HEK293 Cells MeSH
- Hematologic Diseases genetics MeSH
- Humans MeSH
- Mutation, Missense MeSH
- DNA Mutational Analysis MeSH
- Child, Preschool MeSH
- Proto-Oncogene Proteins c-ets genetics MeSH
- Repressor Proteins genetics MeSH
- Pedigree MeSH
- Thrombocytopenia genetics MeSH
- Germ-Line Mutation MeSH
- Check Tag
- Adult MeSH
- Humans MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
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.
Children's Hospital of Michigan Department of Pediatrics Wayne State University Detroit Michigan USA
Department of Biochemistry and Molecular Genetics University of Colorado AMC Aurora Colorado USA
Department of Internal Medicine Haematology Oncology University Hospital Brno Brno Czech Republic
Department of Pathology University of Colorado AMC Aurora Colorado USA
Department of Pediatrics University of Colorado Anschutz Medical Campus Aurora Colorado USA
Program in Cell Biology Research Institute The Hospital for Sick Children Toronto Ontario Canada
References provided by Crossref.org
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