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

Inga Hofmann, Mitchell J Geer, Timo Vögtle, 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, Michael Douglas, Kathleen Freson, Corinne Pondarré, Rémi Favier, Gavin E Jarvis, Kyriacos MarkianosErnest Turro, Willem H Ouwehand, Alexandra Mazharian, Mark D Fleming, Yotis A Senis

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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 Sept 2018


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


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