Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

Irina Pleines, Joanne Woods, Stephane Chappaz, Verity Kew, Nicola Foad, José Ballester-Beltrán, Katja Aurbach, Chiara Lincetto, Rachael M. Lane, Galina Schevzov, Warren S. Alexander, Douglas J. Hilton, William J. Astle, Kate Downes, Paquita Nurden, Sarah K. Westbury, Andrew D. Mumford, Samya G. Obaji, Peter W. Collins, Nihr BioResource & 11 others Fabien Delerue, Lars M. Ittner, Nicole S. Bryce, Mira Holliday, Christine A. Lucas, Edna C. Hardeman, Willem H. Ouwehand, Peter W. Gunning, Ernest Turro, Marloes R. Tijssen, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

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.

Original languageEnglish
Pages (from-to)814-829
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number3
DOIs
Publication statusPublished - 1 Mar 2017
Externally publishedYes

Cite this

Pleines, I., Woods, J., Chappaz, S., Kew, V., Foad, N., Ballester-Beltrán, J., ... Kile, B. T. (2017). Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. Journal of Clinical Investigation, 127(3), 814-829. https://doi.org/10.1172/JCI86154
Pleines, Irina ; Woods, Joanne ; Chappaz, Stephane ; Kew, Verity ; Foad, Nicola ; Ballester-Beltrán, José ; Aurbach, Katja ; Lincetto, Chiara ; Lane, Rachael M. ; Schevzov, Galina ; Alexander, Warren S. ; Hilton, Douglas J. ; Astle, William J. ; Downes, Kate ; Nurden, Paquita ; Westbury, Sarah K. ; Mumford, Andrew D. ; Obaji, Samya G. ; Collins, Peter W. ; BioResource, Nihr ; Delerue, Fabien ; Ittner, Lars M. ; Bryce, Nicole S. ; Holliday, Mira ; Lucas, Christine A. ; Hardeman, Edna C. ; Ouwehand, Willem H. ; Gunning, Peter W. ; Turro, Ernest ; Tijssen, Marloes R. ; Kile, Benjamin T. / Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 3. pp. 814-829.
@article{e515e685f6274a7697940643d67c9b54,
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.",
author = "Irina Pleines and Joanne Woods and Stephane Chappaz and Verity Kew and Nicola Foad and Jos{\'e} Ballester-Beltr{\'a}n and Katja Aurbach and Chiara Lincetto and Lane, {Rachael M.} and Galina Schevzov and Alexander, {Warren S.} and Hilton, {Douglas J.} and Astle, {William J.} and Kate Downes and Paquita Nurden and Westbury, {Sarah K.} and Mumford, {Andrew D.} and Obaji, {Samya G.} and Collins, {Peter W.} and Nihr BioResource and Fabien Delerue and Ittner, {Lars M.} and Bryce, {Nicole S.} and Mira Holliday and Lucas, {Christine A.} and Hardeman, {Edna C.} and Ouwehand, {Willem H.} and Gunning, {Peter W.} and Ernest Turro and Tijssen, {Marloes R.} and Kile, {Benjamin T.}",
year = "2017",
month = "3",
day = "1",
doi = "10.1172/JCI86154",
language = "English",
volume = "127",
pages = "814--829",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "American Society for Clinical Investigation",
number = "3",

}

Pleines, I, Woods, J, Chappaz, S, Kew, V, Foad, N, Ballester-Beltrán, J, Aurbach, K, Lincetto, C, Lane, RM, Schevzov, G, Alexander, WS, Hilton, DJ, Astle, WJ, Downes, K, Nurden, P, Westbury, SK, Mumford, AD, Obaji, SG, Collins, PW, BioResource, N, Delerue, F, Ittner, LM, Bryce, NS, Holliday, M, Lucas, CA, Hardeman, EC, Ouwehand, WH, Gunning, PW, Turro, E, Tijssen, MR & Kile, BT 2017, 'Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia', Journal of Clinical Investigation, vol. 127, no. 3, pp. 814-829. https://doi.org/10.1172/JCI86154

Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. / Pleines, Irina; Woods, Joanne; Chappaz, Stephane; Kew, Verity; Foad, Nicola; Ballester-Beltrán, José; Aurbach, Katja; Lincetto, Chiara; Lane, Rachael M.; Schevzov, Galina; Alexander, Warren S.; Hilton, Douglas J.; Astle, William J.; Downes, Kate; Nurden, Paquita; Westbury, Sarah K.; Mumford, Andrew D.; Obaji, Samya G.; Collins, Peter W.; BioResource, Nihr; Delerue, Fabien; Ittner, Lars M.; Bryce, Nicole S.; Holliday, Mira; Lucas, Christine A.; Hardeman, Edna C.; Ouwehand, Willem H.; Gunning, Peter W.; Turro, Ernest; Tijssen, Marloes R.; Kile, Benjamin T.

In: Journal of Clinical Investigation, Vol. 127, No. 3, 01.03.2017, p. 814-829.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

AU - Pleines, Irina

AU - Woods, Joanne

AU - Chappaz, Stephane

AU - Kew, Verity

AU - Foad, Nicola

AU - Ballester-Beltrán, José

AU - Aurbach, Katja

AU - Lincetto, Chiara

AU - Lane, Rachael M.

AU - Schevzov, Galina

AU - Alexander, Warren S.

AU - Hilton, Douglas J.

AU - Astle, William J.

AU - Downes, Kate

AU - Nurden, Paquita

AU - Westbury, Sarah K.

AU - Mumford, Andrew D.

AU - Obaji, Samya G.

AU - Collins, Peter W.

AU - BioResource, Nihr

AU - Delerue, Fabien

AU - Ittner, Lars M.

AU - Bryce, Nicole S.

AU - Holliday, Mira

AU - Lucas, Christine A.

AU - Hardeman, Edna C.

AU - Ouwehand, Willem H.

AU - Gunning, Peter W.

AU - Turro, Ernest

AU - Tijssen, Marloes R.

AU - Kile, Benjamin T.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85015930553&partnerID=8YFLogxK

U2 - 10.1172/JCI86154

DO - 10.1172/JCI86154

M3 - Article

VL - 127

SP - 814

EP - 829

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 3

ER -