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 Markianos, Ernest Turro, Willem H. Ouwehand, Alexandra Mazharian, Mark D. Fleming and Yotis A. Senis

Key Points

  • Autosomal recessive loss-of-function mutations in G6b-B (MPIG6B) cause congenital macrothrombocytopenia with focal myelofibrosis.

  • G6b-B has orthologous physiological functions in human and mice regulating megakaryocyte and platelet production and function.

Publisher's Note: There is a Blood Commentary on this article in this issue.


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.

  • Submitted August 22, 2017.
  • Accepted June 5, 2018.
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