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

Research output: Contribution to journalArticlepeer-review


  • Inga Hofmann
  • Mitchell J Geer
  • Andrew Crispin
  • Dean R Campagna
  • Alastair Barr
  • Monica L Calicchio
  • Silke Heising
  • Johanna P van Geffen
  • Marijke J E Kuijpers
  • Johan W M Heemskerk
  • Johannes A Eble
  • Klaus Schmitz-Abe
  • Esther A Obeng
  • Kathleen Freson
  • Corinne Pondarré
  • Rémi Favier
  • Gavin E Jarvis
  • Kyriacos Markianos
  • Ernest Turro
  • Willem H Ouwehand
  • Mark D Fleming

External organisations

  • University of Wisconsin-Madison
  • Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
  • Department of Pathology, Boston Children's Hospital, Boston, MA, United States.
  • Department of Biomedical Science, University of Westminster, London, United Kingdom.
  • Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Netherlands.
  • Institute of Physiological Chemistry and Pathobiochemistry, University of Munster, Munster, Germany.
  • Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, United States.
  • Harvard Medical School
  • Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
  • Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Sciences; University of Leuven; Leuven Belgium
  • Department of Pediatrics and INSERM Unite 955, Paris-Est Creteil University, Creteil, France.
  • Service d'Hematologie Biologique, Assistance Publique-Hopitaux de Paris, French reference centre for platelet disorders, Paris, France.
  • University of Cambridge


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 germline 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.


Original languageEnglish
Pages (from-to)1399–1412
Number of pages14
Issue number13
Early online date13 Jun 2018
Publication statusPublished - 27 Sep 2018


  • Myelofibrosis, Congenital myelofibrosis, Familial myelofibrosis, Myeloproliferative neoplasm, C6orf25, MPIG6B, G6b-B, Megakaryocytes, Platelets, Thrombocytopenia, Transgenic mouse