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A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss.
- Source :
-
Blood [Blood] 2016 Jun 09; Vol. 127 (23), pp. 2903-14. Date of Electronic Publication: 2016 Feb 24. - Publication Year :
- 2016
-
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.<br /> (© 2016 by The American Society of Hematology.)
- Subjects :
- A549 Cells
Adolescent
Adult
Aged
Case-Control Studies
Cells, Cultured
Child
Female
Formins
Genetic Association Studies
Genetic Predisposition to Disease
HEK293 Cells
Hearing Loss complications
Humans
Male
Middle Aged
Pedigree
Polymorphism, Single Nucleotide
Syndrome
Thrombocytopenia complications
Young Adult
Adaptor Proteins, Signal Transducing genetics
Hearing Loss genetics
Mutation
Thrombocytopenia genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 127
- Issue :
- 23
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 26912466
- Full Text :
- https://doi.org/10.1182/blood-2015-10-675629