title: A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss.
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.
authors.affiliation: Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, University of Würzburg, Würzburg, Germany;
authors.forename: Simon
authors.initials: S
authors.lastname: Stritt
authors.affiliation: 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;
authors.forename: Paquita
authors.initials: P
authors.lastname: Nurden
authors.affiliation: 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;
authors.forename: Ernest
authors.initials: E
authors.lastname: Turro
authors.affiliation: 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;
authors.forename: Daniel
authors.initials: D
authors.lastname: Greene
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Sjoert B
authors.initials: SB
authors.lastname: Jansen
authors.affiliation: School of Clinical Sciences, University of Bristol, Bristol, United Kingdom;
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Westbury
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Romina
authors.initials: R
authors.lastname: Petersen
authors.affiliation: 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;
authors.forename: William J
authors.initials: WJ
authors.lastname: Astle
authors.affiliation: Centre de Référence des Surdités Génétiques, Service de Génétique Médicale, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marlin
authors.affiliation: 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;
authors.forename: Tadbir K
authors.initials: TK
authors.lastname: Bariana
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Myrto
authors.initials: M
authors.lastname: Kostadima
authors.affiliation: 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;
authors.forename: Claire
authors.initials: C
authors.lastname: Lentaigne
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Stephanie
authors.initials: S
authors.lastname: Maiwald
authors.affiliation: 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;
authors.forename: Sofia
authors.initials: S
authors.lastname: Papadia
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Anne M
authors.initials: AM
authors.lastname: Kelly
authors.affiliation: Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Stephens
authors.affiliation: 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;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Penkett
authors.affiliation: 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;
authors.forename: Sofie
authors.initials: S
authors.lastname: Ashford
authors.affiliation: 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;
authors.forename: Salih
authors.initials: S
authors.lastname: Tuna
authors.affiliation: Department of Haematology, Guy's and St Thomas' National Health Service Foundation Trust, London, United Kingdom;
authors.forename: Steve
authors.initials: S
authors.lastname: Austin
authors.affiliation: Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany;
authors.forename: Tamam
authors.initials: T
authors.lastname: Bakchoul
authors.affiliation: Arthur Bloom Haemophilia Centre, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, United Kingdom;
authors.forename: Peter
authors.initials: P
authors.lastname: Collins
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Armand Trousseau Children Hospital, Paris, France; INSERM U1170, Villejuif, France;
authors.forename: Rémi
authors.initials: R
authors.lastname: Favier
authors.affiliation: Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;
authors.forename: Michele P
authors.initials: MP
authors.lastname: Lambert
authors.affiliation: Department of Haematology, Great Ormond Street Hospital for Children National Health Service Foundation Trust, London, United Kingdom;
authors.forename: Mary
authors.initials: M
authors.lastname: Mathias
authors.affiliation: 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;
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Millar
authors.affiliation: 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;
authors.forename: Rutendo
authors.initials: R
authors.lastname: Mapeta
authors.affiliation: Department of Haematology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: David J
authors.initials: DJ
authors.lastname: Perry
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;
authors.forename: Sol
authors.initials: S
authors.lastname: Schulman
authors.affiliation: 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;
authors.forename: Ilenia
authors.initials: I
authors.lastname: Simeoni
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
authors.forename: Chantal
authors.initials: C
authors.lastname: Thys
authors.affiliation: The Katharine Dormandy Haemophilia Centre and Thrombosis Unit, Royal Free London National Health Service Foundation Trust, London, United Kingdom;
authors.forename: Keith
authors.initials: K
authors.lastname: Gomez
authors.affiliation: Pathology and Laboratory Medicine, University of Western Australia, Crawley, WA, Australia;
authors.forename: Wendy N
authors.initials: WN
authors.lastname: Erber
authors.affiliation: 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;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Stirrups
authors.affiliation: Genomics England Ltd, London, United Kingdom;
authors.forename: Augusto
authors.initials: A
authors.lastname: Rendon
authors.affiliation: 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;
authors.forename: John R
authors.initials: JR
authors.lastname: Bradley
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
authors.forename: Chris
authors.initials: C
authors.lastname: van Geet
authors.affiliation: 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;
authors.forename: F Lucy
authors.initials: FL
authors.lastname: Raymond
authors.affiliation: 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;
authors.forename: Michael A
authors.initials: MA
authors.lastname: Laffan
authors.affiliation: 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;
authors.forename: Alan T
authors.initials: AT
authors.lastname: Nurden
authors.affiliation: Department of Experimental Biomedicine, University Hospital, Rudolf Virchow Center, University of Würzburg, Würzburg, Germany;
authors.forename: Bernhard
authors.initials: B
authors.lastname: Nieswandt
authors.affiliation: Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, United Kingdom;
authors.forename: Sylvia
authors.initials: S
authors.lastname: Richardson
authors.affiliation: Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium;
authors.forename: Kathleen
authors.initials: K
authors.lastname: Freson
authors.affiliation: 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.
authors.forename: Willem H
authors.initials: WH
authors.lastname: Ouwehand
authors.affiliation: School of Cellular and Molecular Medicine, University of Bristol, Bristol, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D005260:Female; D000080865:Formins; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D034381:Hearing Loss / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D013921:Thrombocytopenia / Q000150:complications / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D000080865:Formins