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

• Published in: Nature genetics Vol. 47; no. 5; pp. 535 - 538
• Main Authors: Noetzli, Leila, Lo, Richard W, Lee-Sherick, Alisa B, Callaghan, Michael, Noris, Patrizia, Savoia, Anna, Rajpurkar, Madhvi, Jones, Kenneth, Gowan, Katherine, Balduini, Carlo L, Pecci, Alessandro, Gnan, Chiara, De Rocco, Daniela, Doubek, Michael, Li, Ling, Lu, Lily, Leung, Richard, Landolt-Marticorena, Carolina, Hunger, Stephen, Heller, Paula, Gutierrez-Hartmann, Arthur, Xiayuan, Liang, Pluthero, Fred G, Rowley, Jesse W, Weyrich, Andrew S, Kahr, Walter H A, Porter, Christopher C, Di Paola, Jorge
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-05-2015; Nature Publishing Group
• Subjects: 13/51; 14/19; 38/22; 38/39; 45/22; 45/23; 692/699/1541; Adult; Agriculture; Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Blood; Blood platelets; Cancer Research; Child, Preschool; Deoxyribonucleic acid; Disease susceptibility; DNA; DNA Mutational Analysis; Erythrocytes, Abnormal; ETS Translocation Variant 6 Protein; Exome; Female; Gene Function; Gene mutations; Genetic aspects; Genetic Association Studies; Genetic Predisposition to Disease; Genomes; Germ-Line Mutation; Health aspects; HEK293 Cells; Hematologic Diseases - genetics; Human Genetics; Humans; letter; Leukemia; Lymphocytic leukemia; Male; Mutation; Mutation, Missense; Pedigree; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Proteins; Proto-Oncogene Proteins c-ets - genetics; Repressor Proteins - genetics; Risk factors; Thrombocytopenia - genetics; Transcription factors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3253

Jorge Di Paola, Christopher Porter, Walter Kahr and colleagues report germline mutations in the transcriptional repressor gene
ETV6
in three families with thrombocytopenia and elevated red blood cell volume. All three mutations affect the ability of ETV6 to repress transcription of a reporter construct, and the two protein-altering mutations affect megakaryocyte development.
Some familial platelet disorders are associated with predisposition to leukemia, myelodysplastic syndrome (MDS) or dyserythropoietic anemia
1
,
2
. 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
(
et
s 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.