A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

Simon Stritt, Paquita Nurden, Ernest Turro, Daniel Greene, Sjoert B. Jansen, Sarah K. Westbury, Romina Petersen, William J. Astle, Sandrine Marlin, Tadbir K. Bariana, Myrto Kostadima, Claire Lentaigne, Stephanie Maiwald, Sofia Papadia, Anne M. Kelly, Jonathan C. Stephens, Christopher J. Penkett, Sofie Ashford, Salih Tuna, Steve Austin & 26 others Tamam Bakchoul, Peter Collins, Remi Favier, Michele P. Lambert, Mary Mathias, Carolyn M. Millar, Rutendo Mapeta, David J. Perry, Sol Schulman, Ilenia Simeoni, Chantal Thys, Keith Gomez, Wendy N. Erber, Kathleen Stirrups, Augusto Rendon, John R. Bradley, Chris van Geet, F. Lucy Raymond, Michael A. Laffan, Alan T. Nurden, Bernhard Nieswandt, Sylvia Richardson, Kathleen Freson, Willem H. Ouwehand, Andrew D. Mumford, BRIDGE-BPD Consortium

    Research output: Contribution to journalArticle

    49 Citations (Scopus)

    Abstract

    Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.

    Original languageEnglish
    Pages (from-to)2903-2914
    Number of pages12
    JournalBlood
    Volume127
    Issue number23
    DOIs
    Publication statusPublished - 9 Jun 2016

    Cite this

    Stritt, S., Nurden, P., Turro, E., Greene, D., Jansen, S. B., Westbury, S. K., ... BRIDGE-BPD Consortium (2016). A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood, 127(23), 2903-2914. https://doi.org/10.1182/blood-2015-10-675629
    Stritt, Simon ; Nurden, Paquita ; Turro, Ernest ; Greene, Daniel ; Jansen, Sjoert B. ; Westbury, Sarah K. ; Petersen, Romina ; Astle, William J. ; Marlin, Sandrine ; Bariana, Tadbir K. ; Kostadima, Myrto ; Lentaigne, Claire ; Maiwald, Stephanie ; Papadia, Sofia ; Kelly, Anne M. ; Stephens, Jonathan C. ; Penkett, Christopher J. ; Ashford, Sofie ; Tuna, Salih ; Austin, Steve ; Bakchoul, Tamam ; Collins, Peter ; Favier, Remi ; Lambert, Michele P. ; Mathias, Mary ; Millar, Carolyn M. ; Mapeta, Rutendo ; Perry, David J. ; Schulman, Sol ; Simeoni, Ilenia ; Thys, Chantal ; Gomez, Keith ; Erber, Wendy N. ; Stirrups, Kathleen ; Rendon, Augusto ; Bradley, John R. ; van Geet, Chris ; Raymond, F. Lucy ; Laffan, Michael A. ; Nurden, Alan T. ; Nieswandt, Bernhard ; Richardson, Sylvia ; Freson, Kathleen ; Ouwehand, Willem H. ; Mumford, Andrew D. ; BRIDGE-BPD Consortium. / A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. In: Blood. 2016 ; Vol. 127, No. 23. pp. 2903-2914.
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    abstract = "Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.",
    keywords = "INHERITED THROMBOCYTOPENIAS, PROPLATELET FORMATION, PLATELET FORMATION, CONGENITAL MACROTHROMBOCYTOPENIA, MEGAKARYOCYTE MATURATION, FORMIN MDIA1, MYOSIN IIA, ACTIN, RHO, MICROTUBULES",
    author = "Simon Stritt and Paquita Nurden and Ernest Turro and Daniel Greene and Jansen, {Sjoert B.} and Westbury, {Sarah K.} and Romina Petersen and Astle, {William J.} and Sandrine Marlin and Bariana, {Tadbir K.} and Myrto Kostadima and Claire Lentaigne and Stephanie Maiwald and Sofia Papadia and Kelly, {Anne M.} and Stephens, {Jonathan C.} and Penkett, {Christopher J.} and Sofie Ashford and Salih Tuna and Steve Austin and Tamam Bakchoul and Peter Collins and Remi Favier and Lambert, {Michele P.} and Mary Mathias and Millar, {Carolyn M.} and Rutendo Mapeta and Perry, {David J.} and Sol Schulman and Ilenia Simeoni and Chantal Thys and Keith Gomez and Erber, {Wendy N.} and Kathleen Stirrups and Augusto Rendon and Bradley, {John R.} and {van Geet}, Chris and Raymond, {F. Lucy} and Laffan, {Michael A.} and Nurden, {Alan T.} and Bernhard Nieswandt and Sylvia Richardson and Kathleen Freson and Ouwehand, {Willem H.} and Mumford, {Andrew D.} and {BRIDGE-BPD Consortium}",
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    Stritt, S, Nurden, P, Turro, E, Greene, D, Jansen, SB, Westbury, SK, Petersen, R, Astle, WJ, Marlin, S, Bariana, TK, Kostadima, M, Lentaigne, C, Maiwald, S, Papadia, S, Kelly, AM, Stephens, JC, Penkett, CJ, Ashford, S, Tuna, S, Austin, S, Bakchoul, T, Collins, P, Favier, R, Lambert, MP, Mathias, M, Millar, CM, Mapeta, R, Perry, DJ, Schulman, S, Simeoni, I, Thys, C, Gomez, K, Erber, WN, Stirrups, K, Rendon, A, Bradley, JR, van Geet, C, Raymond, FL, Laffan, MA, Nurden, AT, Nieswandt, B, Richardson, S, Freson, K, Ouwehand, WH, Mumford, AD & BRIDGE-BPD Consortium 2016, 'A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss' Blood, vol. 127, no. 23, pp. 2903-2914. https://doi.org/10.1182/blood-2015-10-675629

    A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. / Stritt, Simon; Nurden, Paquita; Turro, Ernest; Greene, Daniel; Jansen, Sjoert B.; Westbury, Sarah K.; Petersen, Romina; Astle, William J.; Marlin, Sandrine; Bariana, Tadbir K.; Kostadima, Myrto; Lentaigne, Claire; Maiwald, Stephanie; Papadia, Sofia; Kelly, Anne M.; Stephens, Jonathan C.; Penkett, Christopher J.; Ashford, Sofie; Tuna, Salih; Austin, Steve; Bakchoul, Tamam; Collins, Peter; Favier, Remi; Lambert, Michele P.; Mathias, Mary; Millar, Carolyn M.; Mapeta, Rutendo; Perry, David J.; Schulman, Sol; Simeoni, Ilenia; Thys, Chantal; Gomez, Keith; Erber, Wendy N.; Stirrups, Kathleen; Rendon, Augusto; Bradley, John R.; van Geet, Chris; Raymond, F. Lucy; Laffan, Michael A.; Nurden, Alan T.; Nieswandt, Bernhard; Richardson, Sylvia; Freson, Kathleen; Ouwehand, Willem H.; Mumford, Andrew D.; BRIDGE-BPD Consortium.

    In: Blood, Vol. 127, No. 23, 09.06.2016, p. 2903-2914.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

    AU - Stritt, Simon

    AU - Nurden, Paquita

    AU - Turro, Ernest

    AU - Greene, Daniel

    AU - Jansen, Sjoert B.

    AU - Westbury, Sarah K.

    AU - Petersen, Romina

    AU - Astle, William J.

    AU - Marlin, Sandrine

    AU - Bariana, Tadbir K.

    AU - Kostadima, Myrto

    AU - Lentaigne, Claire

    AU - Maiwald, Stephanie

    AU - Papadia, Sofia

    AU - Kelly, Anne M.

    AU - Stephens, Jonathan C.

    AU - Penkett, Christopher J.

    AU - Ashford, Sofie

    AU - Tuna, Salih

    AU - Austin, Steve

    AU - Bakchoul, Tamam

    AU - Collins, Peter

    AU - Favier, Remi

    AU - Lambert, Michele P.

    AU - Mathias, Mary

    AU - Millar, Carolyn M.

    AU - Mapeta, Rutendo

    AU - Perry, David J.

    AU - Schulman, Sol

    AU - Simeoni, Ilenia

    AU - Thys, Chantal

    AU - Gomez, Keith

    AU - Erber, Wendy N.

    AU - Stirrups, Kathleen

    AU - Rendon, Augusto

    AU - Bradley, John R.

    AU - van Geet, Chris

    AU - Raymond, F. Lucy

    AU - Laffan, Michael A.

    AU - Nurden, Alan T.

    AU - Nieswandt, Bernhard

    AU - Richardson, Sylvia

    AU - Freson, Kathleen

    AU - Ouwehand, Willem H.

    AU - Mumford, Andrew D.

    AU - BRIDGE-BPD Consortium

    PY - 2016/6/9

    Y1 - 2016/6/9

    N2 - Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.

    AB - Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.

    KW - INHERITED THROMBOCYTOPENIAS

    KW - PROPLATELET FORMATION

    KW - PLATELET FORMATION

    KW - CONGENITAL MACROTHROMBOCYTOPENIA

    KW - MEGAKARYOCYTE MATURATION

    KW - FORMIN MDIA1

    KW - MYOSIN IIA

    KW - ACTIN

    KW - RHO

    KW - MICROTUBULES

    U2 - 10.1182/blood-2015-10-675629

    DO - 10.1182/blood-2015-10-675629

    M3 - Article

    VL - 127

    SP - 2903

    EP - 2914

    JO - Blood

    JF - Blood

    SN - 0006-4971

    IS - 23

    ER -

    Stritt S, Nurden P, Turro E, Greene D, Jansen SB, Westbury SK et al. A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss. Blood. 2016 Jun 9;127(23):2903-2914. https://doi.org/10.1182/blood-2015-10-675629