Work

An iPSC model of thrombocytopenia-absent radius syndrome links aberrant splicing to impaired megakaryopoiesis

Year: 2026

Type: article

Abstract: Thrombocytopenia absent radius (TAR) syndrome is a rare disease characterized by thrombocytopenia that results from defective differentiation of megakaryocyte (MK) precursors. It is caused by mutations in the exon junction complex member, RBM8A , but it is not understood how the deficiency in this gene leads to a defect in megakaryopoiesis. Using TAR patient-derived induced pluripotent stem cell (iPSC) lines and isogenic lines with corrected expression of RBM8A , we compared the phenotypes of derivative hematopoietic progenitor cells (HPC) and MKs. While the generation of HPCs was similar between lines, the proliferation of TAR MKs was significantly reduced. This was accompanied by precocious maturation, differential expression of platelet signaling pathways, and enhanced apoptosis. Despite TAR MK’s enhanced size and markers of maturation, TAR and corrected lines had similar platelet-forming capacity both in vitro and in vivo . Genome-wide gene expression analysis revealed differential gene expression in apoptosis and cell cycle pathways. Splicing analysis showed differential splicing of pathways involved in mRNA splicing as well as platelet degranulation, demonstrating lineage-specific defects. We also identified several candidate targets that could be contributing to the phenotypes observed in this model. Overall, our study shows that the thrombocytopenia in TAR syndrome results from the lack of proliferation and increased cell death of MK progenitors, leading to fewer numbers of mature MKs and platelets.

Source: Blood Vessels Thrombosis & Hemostasis

DOI: 10.1016/j.bvth.2026.100201