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Blood. 2018 Sep 27;132(13):1399-1412. doi: 10.1182/blood-2017-08-802769. Epub 2018 Jun 13.

Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice.

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Division of Hematology, Oncology, and Bone Marrow Transplantation, Department of Pediatrics, University of Wisconsin, Madison, WI.
Department of Pathology, Boston Children's Hospital, Boston, MA.
Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Department of Biomedical Science, University of Westminster, London, United Kingdom.
Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Institute of Physiological Chemistry and Pathobiochemistry, University of Münster, Münster, Germany.
Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA.
Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Harvard Medical School, Boston, MA.
Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Department of Neurology, Russells Hall Hospital, Dudley Group National Health Service (NHS) Foundation Trust, Dudley, United Kingdom.
School of Life and Health Sciences, Aston University, Birmingham, United Kingdom.
Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium.
Service de pédiatrie, Centre de référence de la Drépanocytose, Centre Hospitalier Intercommunal de Créteil (CHIC), Créteil, France.
INSERM Unité 955, University Paris-Est Créteil, Créteil, France.
Assistance Publique-Hôpitaux de Paris, A Trousseau children hospital, French reference centre for platelet disorders, Paris, France.
Gustave Roussy Institute, Unité Mixte de Recherche (UMR) 1170, Villejuif, France.
Department of Physiology, Development and Neuroscience.
Department of Haematology, and.
MRC Biostatistics Unit, University of Cambridge, Cambridge, United Kingdom.
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom.
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; and.
NHS Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom.


Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor.

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