Thrombocytopenia, Anemia, And Myelofibrosis

A number sign (#) is used with this entry because of evidence that thrombocytopenia, anemia, and myelofibrosis (THAMY; 617441) is caused by homozygous mutation in the G6B gene (MPIG6B; 606520) on chromosome 6p21. One such family has been reported.

Clinical Features

Melhem et al. (2016) reported 4 adult sibs, born of consanguineous Arab parents, with persistent thrombocytopenia and anemia since early childhood. Two of the patients had significant splenomegaly associated with the lowest hemoglobin levels. Apart from bruising, there was no history of major bleeding. White blood cell counts were always normal, and none had a history of increased infections. Peripheral blood smear showed severe thrombocytopenia and increased numbers of giant platelets. Red blood cells showed moderate anisopoikilocytosis with tear drop shape and rare nucleated red blood cells and neutrophil precursors. Bone marrow biopsies showed increased numbers of megakaryocytes and moderate-to-severe reticular fibrosis consistent with a myeloproliferative disorder most compatible with myelofibrosis. Treatment was limited to iron and B12/folic acid supplements; occasional transfusions were given when needed.

Inheritance

The transmission pattern of THAMY in the family reported by Melhem et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 sibs, born of consanguineous Arab parents, with THAMY, Melhem et al. (2016) identified a homozygous truncating mutation in the G6B gene (C108X; 606520.0001). The mutation was found by a combination of linkage analysis and exome sequencing and was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family. In vitro functional expression studies in K562 human chronic myelogenous leukemia cells showed that the mutant protein was unstable. The truncated protein was unable to enhance K562 differentiation into megakaryocytes and erythrocytes after stimulation compared to wildtype.

Animal Model

Mazharian et al. (2012) found that G6b-null mice developed macrothrombocytopenia and had a bleeding diathesis due to defective platelet production and function. Mutant mice showed increased platelet turnover and increased platelet clearance, including antibody-mediated clearance, associated with enlarged spleens, myelofibrosis, and extramedullary hematopoiesis. Bone marrow-derived mutant megakaryocytes showed reduced spreading and reduced branched proplatelets on fibrinogen- or fibronectin-coated surfaces compared to controls, suggesting defective outside-in integrin signaling and defective microtubule extension and actin-mediated branching. Mutant platelets had altered organelle and granule content, and both platelets and megakaryocytes had defective surface glycoprotein abundance. The findings indicated that G6B is a critical regulator of megakaryocyte function and platelet production.