title: Germline mutations in ETV6 are associated with thrombocytopenia, red cell macrocytosis and predisposition to lymphoblastic leukemia.
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.
authors: Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, CO, USA.|Human Medical Genetics and Genomics Program, University of Colorado AMC, Aurora, Colorado, USA.
authors: Leila
authors: L
authors: Noetzli
authors: Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.
authors: Richard W
authors: RW
authors: Lo
authors: Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, CO, USA.
authors: Alisa B
authors: AB
authors: Lee-Sherick
authors: Children's Hospital of Michigan, Wayne State University, Detroit, MI, USA.
authors: Michael
authors: M
authors: Callaghan
authors: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy.
authors: Patrizia
authors: P
authors: Noris
authors: Department of Medical Sciences, University of Trieste, Trieste, Italy.|Institute for Maternal and Child Health- IRCCS Burlo Garofolo, Trieste, Italy.
authors: Anna
authors: A
authors: Savoia
authors: Children's Hospital of Michigan, Wayne State University, Detroit, MI, USA.
authors: Madhvi
authors: M
authors: Rajpurkar
authors: Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, Colorado, USA.
authors: Kenneth
authors: K
authors: Jones
authors: Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, Colorado, USA.
authors: Katherine
authors: K
authors: Gowan
authors: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy.
authors: Carlo
authors: C
authors: Balduini
authors: Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy.
authors: Alessandro
authors: A
authors: Pecci
authors: Department of Medical Sciences, University of Trieste, Trieste, Italy.|Institute for Maternal and Child Health- IRCCS Burlo Garofolo, Trieste, Italy.
authors: Chiara
authors: C
authors: Gnan
authors: Department of Medical Sciences, University of Trieste, Trieste, Italy.|Institute for Maternal and Child Health- IRCCS Burlo Garofolo, Trieste, Italy.
authors: Daniela
authors: D
authors: De Rocco
authors: Department of Internal Medicine, Haematology/Oncology, University Hospital Brno, CZ.
authors: Michael
authors: M
authors: Doubek
authors: Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Ling
authors: L
authors: Li
authors: Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Lily
authors: L
authors: Lu
authors: Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Richard
authors: R
authors: Leung
authors: Department of Medicine, University of Toronto, Division of Rheumatology University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada.
authors: Carolina
authors: C
authors: Landolt-Marticorena
authors: Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, CO, USA.
authors: Stephen
authors: S
authors: Hunger
authors: Instituto de Investigaciones Medicas Alfredo Lanari, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors: Paula
authors: P
authors: Heller
authors: Department of Biochemistry and Molecular Genetics, University of Colorado AMC, Aurora, Colorado, USA.|Departments of Medicine, University of Colorado, AMC, Aurora, Colorado, USA.
authors: Arthur
authors: A
authors: Gutierrez-Hartmann
authors: Department of Pathology, University of Colorado, AMC, Aurora, Colorado, USA.
authors: Liang
authors: L
authors: Xiayuan
authors: Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Fred G
authors: FG
authors: Pluthero
authors: Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.|Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA.
authors: Jesse W
authors: JW
authors: Rowley
authors: Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.|Molecular Medicine Program, University of Utah, Salt Lake City, Utah, USA.
authors: Andrew S
authors: AS
authors: Weyrich
authors: Program in Cell Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.|Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.|Department of Paediatrics, Division of Haematology/Oncology, University of Toronto and The Hospital for Sick Children, Toronto, Ontario, Canada.
authors: Walter H A
authors: WHA
authors: Kahr
authors: Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, CO, USA.
authors: Christopher C
authors: CC
authors: Porter
authors: Department of Pediatrics, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, CO, USA.|Human Medical Genetics and Genomics Program, University of Colorado AMC, Aurora, Colorado, USA.
authors: Jorge
authors: J
authors: Di Paola
mesh_terms: D000328:Adult; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004913:Erythrocytes, Abnormal; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006402:Hematologic Diseases / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D013921:Thrombocytopenia / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein