title: Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.
abstract: Platelets are anuclear cells that are essential for blood clotting. They are produced by large polyploid precursor cells called megakaryocytes. Previous genome-wide association studies in nearly 70,000 individuals indicated that single nucleotide variants (SNVs) in the gene encoding the actin cytoskeletal regulator tropomyosin 4 (TPM4) exert an effect on the count and volume of platelets. Platelet number and volume are independent risk factors for heart attack and stroke. Here, we have identified 2 unrelated families in the BRIDGE Bleeding and Platelet Disorders (BPD) collection who carry a TPM4 variant that causes truncation of the TPM4 protein and segregates with macrothrombocytopenia, a disorder characterized by low platelet count. N-Ethyl-N-nitrosourea-induced (ENU-induced) missense mutations in Tpm4 or targeted inactivation of the Tpm4 locus led to gene dosage-dependent macrothrombocytopenia in mice. All other blood cell counts in Tpm4-deficient mice were normal. Insufficient TPM4 expression in human and mouse megakaryocytes resulted in a defect in the terminal stages of platelet production and had a mild effect on platelet function. Together, our findings demonstrate a nonredundant role for TPM4 in platelet biogenesis in humans and mice and reveal that truncating variants in TPM4 cause a previously undescribed dominant Mendelian platelet disorder.
authors.forename: Irina
authors.initials: I
authors.lastname: Pleines
authors.forename: Joanne
authors.initials: J
authors.lastname: Woods
authors.forename: Stephane
authors.initials: S
authors.lastname: Chappaz
authors.forename: Verity
authors.initials: V
authors.lastname: Kew
authors.forename: Nicola
authors.initials: N
authors.lastname: Foad
authors.forename: José
authors.initials: J
authors.lastname: Ballester-Beltrán
authors.forename: Katja
authors.initials: K
authors.lastname: Aurbach
authors.forename: Chiara
authors.initials: C
authors.lastname: Lincetto
authors.forename: Rachael M
authors.initials: RM
authors.lastname: Lane
authors.forename: Galina
authors.initials: G
authors.lastname: Schevzov
authors.forename: Warren S
authors.initials: WS
authors.lastname: Alexander
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Hilton
authors.forename: William J
authors.initials: WJ
authors.lastname: Astle
authors.forename: Kate
authors.initials: K
authors.lastname: Downes
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Westbury
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
authors.forename: Samya G
authors.initials: SG
authors.lastname: Obaji
authors.forename: Peter W
authors.initials: PW
authors.lastname: Collins
authors.forename: Fabien
authors.initials: F
authors.lastname: Delerue
authors.forename: Lars M
authors.initials: LM
authors.lastname: Ittner
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Bryce
authors.forename: Mira
authors.initials: M
authors.lastname: Holliday
authors.forename: Christine A
authors.initials: CA
authors.lastname: Lucas
authors.forename: Edna C
authors.initials: EC
authors.lastname: Hardeman
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gunning
authors.forename: Ernest
authors.initials: E
authors.lastname: Turro
authors.forename: Marloes R
authors.initials: MR
authors.lastname: Tijssen
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Kile
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D005799:Genes, Dominant; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D013921:Thrombocytopenia / Q000235:genetics / Q000378:metabolism; D014335:Tropomyosin / Q000235:genetics / Q000378:metabolism
chemical_list: C501213:TPM4 protein, human; D014335:Tropomyosin; C515376:tropomyosin 4 protein, mouse