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

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Stritt, S 
Nurden, P 
Turro, E 
Greene, D 
Jansen, SB 


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.



A549 Cells, Adaptor Proteins, Signal Transducing, Adolescent, Adult, Aged, Case-Control Studies, Cells, Cultured, Child, Female, Genetic Association Studies, Genetic Predisposition to Disease, HEK293 Cells, Hearing Loss, Humans, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Syndrome, Thrombocytopenia, Young Adult

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American Society of Hematology
Medical Research Council (MR/L003120/1)
Medical Research Council (G0800270)
British Heart Foundation (None)
British Heart Foundation (None)
British Heart Foundation (None)
CCF (None)
Medical Research Council (G0800270/1)
The NIHR BioResource- Rare Diseases and the associated BRIDGE genome sequencing projects are supported by the National Institute for Health Research (NIHR; B.N. was supported by the Deutsche Forschungsgemeinschaft (SFB 688). S.S. was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg. ET, DG, JCS, SP, IS, CJP, RM, SAsh, ST and KS are supported by the NIHR BioResource - Rare Diseases. KF, CT, and CVG are supported by the Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium, G.0B17.13N) and by the Research Council of the University of Leuven (BOF KU Leuven‚ Belgium, OT/14/098). WNE is supported by the Cancer Council Western Australia. Research in the Ouwehand laboratory is supported by program grants from the European Commission, NIHR to WJA, SM, MK, RP, SBJ and WHO under numbers RP-PG-0310-1002; the laboratory also receives funding from NHS Blood and Transplant; CL and SKW are supported by Medical Research Council (MRC) Clinical Training Fellowships (number MR/K023489/1) and TKB by a British Society of Haematology/NHS Blood and Transplant grant. MAL and CL are supported by the Imperial College London Biomedical Research Centre; JRB acknowledges support by the NIHR Cambridge Biomedical Research Centre and SR by the Medical Research Council and Cambridge Biomedical Research Centre. CVG is holder of the Bayer and Norbert Heimburger (CSL Behring) Chairs. ADM is supported by the NIHR Bristol Cardiovascular Biomedical Research Unit.