MPIG6B – Thrombocytopenia, Anemia, and Myelofibrosis

Thrombocytopenia, anemia, and myelofibrosis (THAMY) is an exceptionally rare autosomal recessive disorder arising from pathogenic variants in the MPIG6B gene. A 13-year-old male presented with macrothrombocytopenia, anemia, bleeding tendency, and splenomegaly; bone marrow biopsy confirmed focal myelofibrosis and genetic testing revealed homozygous c.523C>T (p.Arg175Ter) in MPIG6B (PMID:38481905).

Subsequent studies report four unrelated probands with homozygous loss-of-function MPIG6B variants: c.523C>T (p.Arg175Ter) (PMID:38481905), c.324C>A (p.Cys108Ter) (PMID:27743390), c.396del (p.Pro134LeufsTer11) (PMID:31276734), and c.420T>A (p.Tyr140Ter) (PMID:35940081). All cases display autosomal recessive inheritance.

Segregation analysis in a consanguineous family confirmed homozygous c.324C>A segregating with thrombocytopenia and anemia in multiple affected relatives (PMID:27743390).

Functionally, G6b-B encodes an immunoglobulin superfamily receptor with two ITIM motifs; it interacts with SHP-1 and SHP-2 to regulate megakaryocyte differentiation. Truncating mutations destabilize G6b-B and impair megakaryocyte and erythroid differentiation in cell models (PMID:27743390) and Shp1/Shp2 double-knockout mice phenocopy the human macrothrombocytopenia and marrow fibrosis (PMID:11544253).

Clinically, allogeneic hematopoietic stem cell transplantation in a 14-year-old girl with homozygous c.420T>A resulted in resolution of cytopenias and myelofibrosis (PMID:35940081).

Integration of genetic and experimental data supports a Strong association between MPIG6B biallelic loss-of-function and THAMY. MPIG6B sequencing is recommended for early diagnosis in patients with congenital macrothrombocytopenia, anemia, and myelofibrosis to guide therapeutic decisions, including stem cell transplantation.

References

• Cureus • 2024 • A Rare MPIG6B Gene Mutation in a Saudi Adolescent Male With Thrombocytopenia, Anemia, and Myelofibrosis: A Case Report. PMID:38481905
• European journal of haematology • 2017 • Novel G6B gene variant causes familial autosomal recessive thrombocytopenia and anemia. PMID:27743390
• Gene • 2019 • Case report of a novel MPIG6B gene mutation in a Chinese boy with pancytopenia and splenomegaly. PMID:31276734
• Current research in translational medicine • 2022 • A novel MPIG6B gene mutation in an adolescent girl with congenital thrombocytopenia and myelofibrosis. PMID:35940081
• The Journal of biological chemistry • 2001 • G6b, a novel immunoglobulin superfamily member encoded in the human major histocompatibility complex, interacts with SHP-1 and SHP-2. PMID:11544253

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