A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss PMID: 26912466

ADC Targets in Oncology

2026-04-10

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

Blood. 2016 Jun 9;127(23):2903-14. doi: 10.1182/blood-2015-10-675629.

Simon Stritt ¹ , Paquita Nurden ² , Ernest Turro ³ , Daniel Greene ⁴ , Sjoert B Jansen ⁵ , Sarah K Westbury ⁶ , Romina Petersen ⁵ , William J Astle ⁷ , Sandrine Marlin ⁸ , Tadbir K Bariana ⁹ , Myrto Kostadima ⁵ , Claire Lentaigne ¹⁰ , Stephanie Maiwald ⁵ , Sofia Papadia ¹¹ , Anne M Kelly ⁵ , Jonathan C Stephens ⁵ , Christopher J Penkett ¹¹ , Sofie Ashford ¹¹ , Salih Tuna ¹¹ , Steve Austin ¹² , Tamam Bakchoul ¹³ , Peter Collins ¹⁴ , Rémi Favier ¹⁵ , Michele P Lambert ¹⁶ , Mary Mathias ¹⁷ , Carolyn M Millar ¹⁰ , Rutendo Mapeta ¹¹ , David J Perry ¹⁸ , Sol Schulman ¹⁹ , Ilenia Simeoni ¹¹ , Chantal Thys ²⁰ , BRIDGE-BPD Consortium , Keith Gomez ²¹ , Wendy N Erber ²² , Kathleen Stirrups ¹¹ , Augusto Rendon ²³ , John R Bradley ²⁴ , Chris van Geet ²⁰ , F Lucy Raymond ²⁵ , Michael A Laffan ¹⁰ , Alan T Nurden ² , Bernhard Nieswandt ¹ , Sylvia Richardson ²⁶ , Kathleen Freson ²⁰ , Willem H Ouwehand ²⁷ , Andrew D Mumford ²⁸

Affiliations

1. Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, University of Würzburg, Würzburg, Germany;
2. Institut 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;
3. Department 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;
4. Department 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;
5. Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
6. School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
7. Department 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;
8. Centre de Référence des Surdités Génétiques, Service de Génétique Médicale, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France;
9. Department 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;
10. Centre 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;
11. Department 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;
12. Department of Haematology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom;
13. Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany;
14. Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom;
15. Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, Paris, France; INSERM U1170, Villejuif, France;
16. Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
17. Department of Haematology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom;
18. Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom;
19. Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
20. Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
21. The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London National Health Service Foundation Trust, London, United Kingdom;
22. Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia;
23. Genomics England Ltd, London, United Kingdom;
24. National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; Research & Development, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, United Kingdom;
25. National 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;
26. Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom;
27. Department 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.
28. School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.

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.