Journal
BLOOD
Volume 127, Issue 23, Pages 2903-2914Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-10-675629
Keywords
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Categories
Funding
- NIHR
- Deutsche Forschungsgemeinschaft [SFB 688]
- German Excellence Initiative
- NIHR BioResource-Rare Diseases
- Fund for Scientific Research-Flanders (FWO-Vlaanderen, Belgium) [G.0B17.13N]
- Research Council of the University of Leuven (Bijzonder Onderzoeksfonds KU Leuven, Belgium) [OT/14/098]
- Cancer Council Western Australia
- European Commission
- NIHR [RP-PG-0310-1002]
- National Health Service Blood and Transplant (NHSBT)
- Medical Research Council [MR/K023489/1]
- British Society of Haematology/NHSBT
- Imperial College London Biomedical Research Centre
- NIHR Cambridge Biomedical Research Centre
- Medical Research Council
- Cambridge Biomedical Research Centre
- Bayer and Norbert Heimburger (CSL Behring) Chairs
- NIHR Bristol Cardiovascular Biomedical Research Unit
- British Heart Foundation [RG/08/014/24067, RG/13/13/30194, RG/09/012/28096] Funding Source: researchfish
- Medical Research Council [MC_UP_0801/1, G0800270, MR/L003120/1, MR/K023489/1, MR/J011711/1] Funding Source: researchfish
- National Institute for Health Research [RP-PG-0310-1002, NF-SI-0513-10151, NF-SI-0512-10165, NF-SI-0512-10014, NF-SI-0510-10214] Funding Source: researchfish
- MRC [G0800270, MC_UP_0801/1, MR/J011711/1, MR/K023489/1, MR/L003120/1] Funding Source: UKRI
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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 (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.
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