ArticleBlood2016
A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss.
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Article in Blood, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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77citing papers in PubMed
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77 citing papers in PubMed, 155 citations in OpenAlex.
- Application of High-Throughput Sequencing in the Diagnosis of Inherited Thrombocytopenia.Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis · 2018Trial
- Hearing loss associated with CDC42 in mice and humans (Takenouchi-Kosaki syndrome): CDC42 and RHOQ synergistically function in cochlear hair cells.The Journal of biological chemistry · 2026Article
- Bleeding Disorders in Children With Genetic Diseases: A Narrative Review.Acta paediatrica (Oslo, Norway : 1992) · 2026Review
- Immune-related actinopathies at the cross-road of immunodeficiency, autoimmunity and autoinflammation.Nature reviews. Immunology · 2026Review
- α-Actinin-1 in Megakaryocytes: Its Structure, Interacting Proteins and Implications for Thrombopoiesis.Biomedicines · 2025Review
- Article
- Negative cooperativity regulates ligand activation of DIAPH1 and other diaphanous related formins.Communications biology · 2025Article
- Inherited deficiency of DIAPH1 identifies a DNA double strand break repair pathway regulated by γ-actin.Nature communications · 2025Article
- Review
- The Use of Next-Generation Sequencing in Personalized Medicine.Methods in molecular biology (Clifton, N.J.) · 2025Review
- A Novel Homozygote Pathogenic Variant in the DIAPH1 Gene Associated With Seizures, Cortical Blindness, and Microcephaly Syndrome (SCBMS): Report of a Family and Literature Review.Molecular genetics & genomic medicine · 2024Review
- DIAPH1-Deficiency is Associated with Major T, NK and ILC Defects in Humans.Journal of clinical immunology · 2024Article
- Article
- Article
- Dynamic actin/septin network in megakaryocytes coordinates proplatelet elaboration.Haematologica · 2024Article
- Immune dysregulation due to bi-allelic mutation of the actin remodeling protein DIAPH1.Frontiers in immunology · 2024Article
- Association between DIAPH1 variant and posterior circulation involvement with Moyamoya disease.Scientific reports · 2023Article
- An Extended Iranian Family with Autosomal Dominant Non-syndromic Hearing Loss Associated with A Nonsense Mutation in theArchives of Iranian medicine · 2023Article
- In-depth genetic and molecular characterization of diaphanous related formin 2 (DIAPH2) and its role in the inner ear.PloS one · 2023Article
- Thymosin β4 is essential for thrombus formation by controlling the G-actin/F-actin equilibrium in platelets.Haematologica · 2022Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
46 authors at 15 institutions in 6 countries.
Simon StrittDepartment of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, University of Würzburg, Würzburg, Germany;
Paquita NurdenInstitut Hospitalo-Universitaire L'Institut de RYthmologie et modélisation Cardiaque, Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France; French Reference Center on Inherited Platelet Disorders, Centre Hospitalier Universitaire Timone, Marseille, France;
Ernest TurroDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Daniel GreeneDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Sjoert B JansenDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Sarah K WestburySchool of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
Romina PetersenDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
William J AstleDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Sandrine MarlinCentre de Référence des Surdités Génétiques, Service de Génétique Médicale, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France;
Tadbir K BarianaDepartment of Haematology, University College London Cancer Institute, London, United Kingdom; The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London National Health Service Foundation Trust, London, United Kingdom;
Myrto KostadimaDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Claire LentaigneCentre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom;
Stephanie MaiwaldDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Sofia PapadiaDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Anne M KellyDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Jonathan C StephensDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Christopher J PenkettDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Sofie AshfordDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Salih TunaDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Steve AustinDepartment of Haematology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom;
Tamam BakchoulInstitute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany;
Peter CollinsArthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom;
Rémi FavierAssistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, Paris, France; INSERM U1170, Villejuif, France;
Michele P LambertDivision of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
Mary MathiasDepartment of Haematology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom;
Carolyn M MillarCentre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom;
Rutendo MapetaDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
David J PerryDepartment of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Sol SchulmanBeth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
Ilenia SimeoniDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Chantal ThysDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
BRIDGE-BPD Consortium
Keith GomezThe Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London National Health Service Foundation Trust, London, United Kingdom;
Wendy N ErberPathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia;
Kathleen StirrupsDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Augusto RendonGenomics England Ltd, London, United Kingdom;
John R BradleyNational Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; Research & Development, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom;
Chris van GeetDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
F Lucy RaymondNational Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom; Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom;
Michael A LaffanCentre for Haematology, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, United Kingdom; Imperial College Healthcare National Health Service Trust, London, United Kingdom;
Alan T NurdenInstitut Hospitalo-Universitaire L'Institut de RYthmologie et modélisation Cardiaque, Plateforme Technologique et d'Innovation Biomédicale, Hôpital Xavier Arnozan, Pessac, France; French Reference Center on Inherited Platelet Disorders, Centre Hospitalier Universitaire Timone, Marseille, France;
Bernhard NieswandtDepartment of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, University of Würzburg, Würzburg, Germany;
Sylvia RichardsonMedical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom;
Kathleen FresonDepartment of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
Willem H OuwehandDepartment of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource-Rare Diseases, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom; Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom; and.
Andrew D MumfordSchool of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
National Health Service · GBUniversity of Cambridge · GBKU Leuven · BEHôpital Xavier Arnozan · FRUniversity of Bristol · GBUniversity of Würzburg · DEBeth Israel Deaconess Medical Center · USCardiff University · GBChildren's Hospital of Philadelphia · USGenomics England · GBHôpital Necker-Enfants Malades · FRInserm · FRMRC Biostatistics Unit · GBThe University of Western Australia · AUUniversitätsmedizin Greifswald · DE
Funding
British Heart Foundation RG/08/014/24067British Heart Foundation RG/09/012/28096British Heart Foundation RG/13/13/30194Department of Health RP-PG-0310-1002Medical Research Council G0800270Medical Research Council MC_UP_0801/1Medical Research Council MR/J011711/1Medical Research Council MR/K023489/1Medical Research Council MR/L003120/1
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.
Indexed as
MutationA549 CellsAdaptor Proteins, Signal TransducingAdolescentAdultAgedCase-Control StudiesCells, CulturedChildFemaleForminsGenetic Association StudiesGenetic Predisposition to DiseaseHearing LossHEK293 CellsHumansAdaptor Proteins, Signal TransducingDIAPH1 protein, humanFormins
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