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 AustinTamam Bakchoul, Peter Collins, Rémi Favier, Michele P Lambert, Mary Mathias, Carolyn M Millar, Rutendo Mapeta, David J Perry, Sol Schulman, Ilenia Simeoni, Chantal Thys, Bridge-Bpd Consortium, 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

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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 (MK). 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 two unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 p.R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was associated with 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. Over-expression 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 insights into the autoregulation of DIAPH1 activity.
Original languageEnglish
Pages (from-to)2903-2914
Number of pages12
Issue number23
Early online date24 Feb 2016
Publication statusPublished - 9 Jun 2016

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