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A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss
Simon Stritt1, Paquita Nurden2, Ernest Turro3
1Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, University of Würzburg, Würzburg, Germany;
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.
Insights
Macrothrombocytopenia (MTP) is a platelet disorder linked to the DIAPH1 gene. A DIAPH1 variant causes MTP and hearing loss by affecting platelet formation and cytoskeletal regulation.
Area of Science:
- Genetics
- Hematology
- Cell Biology
Background:
- Macrothrombocytopenia (MTP) is a group of disorders characterized by enlarged, low-count platelets, often leading to bleeding.
- Altered megakaryocyte (MK) regulation of platelet formation is a common cause of MTP.
- The genetic basis for many MTP cases remains unidentified.
Purpose of the Study:
- To identify candidate genes for MTP using advanced sequencing and phenotyping.
- To investigate the role of DIAPH1 in a novel MTP and hearing loss disorder.
- To elucidate the mechanism of DIAPH1 dysfunction in platelet formation.
Main Methods:
- Exome sequencing and ontological phenotyping were employed to identify candidate genes.
- Two unrelated families with MTP and sensorineural hearing loss were studied.
- DIAPH1 R1213* variant effects were analyzed in cultured MKs and platelets, and via overexpression studies.
Main Results:
- DIAPH1 was identified as a candidate gene for MTP.
- A DIAPH1 R1213* variant, causing partial truncation, was found in families with MTP and hearing loss.
- This variant impaired proplatelet formation, altered actin cytoskeleton, and increased filamentous actin and stable microtubules in platelets, indicating constitutive DIAPH1 activation.
Conclusions:
- The DIAPH1 R1213* variant is linked to a novel disorder of platelet formation and hearing loss.
- This finding expands the spectrum of DIAPH1-related diseases.
- The study provides insights into the autoregulation of DIAPH1 activity and its role in cytoskeletal dynamics.
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