An iPSC model of thrombocytopenia-absent radius syndrome links aberrant splicing to impaired megakaryopoiesis
8 affiliations
- 1Cell and Molecular Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
- 2Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, PA
- 3Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA
- 4Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA
- 5Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge, Cambridge, United Kingdom
- 6Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium
- 7Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine and Children’s Hospital of Philadelphia, Philadelphia, PA
- 8Center for Computational and Genomic Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA
Abstract
Thrombocytopenia-absent radius (TAR) syndrome is a rare disease characterized by thrombocytopenia that results from the defective differentiation of megakaryocyte (MK) precursors. It is caused by mutations in the exon junction complex member RBM8A; however, it is not understood how the deficiency in this gene leads to a defect in megakaryopoiesis. Using induced pluripotent stem cell lines derived from patients with TAR syndrome and isogenic lines with corrected expression of RBM8A, we compared the phenotypes of derivative hematopoietic progenitor cells (HPCs) and MK. Although the generation of HPCs was similar between lines, the proliferation of TAR MK was significantly reduced. This was accompanied by precocious maturation, differential expression of platelet signaling pathways, and enhanced apoptosis. Despite enhanced size and markers of maturation of TAR MK, 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 and platelet degranulation, demonstrating lineage-specific defects. We also identified several candidate targets that could contribute 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 mature MK and platelets.
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BibTeX
@article{nations2026ipsc,
title = {{An iPSC model of thrombocytopenia-absent radius syndrome links aberrant splicing to impaired megakaryopoiesis}},
author = {Catriana C. Nations and Jenea I. Adams and Nicole Debruyne and Xiuli Sim and Hyun Sook Ahn and C. J. Willett and James Warland and Cedric Ghevaert and Kathleen Freson and Giulia Pavani and Deborah L. French and Mortimer Poncz and Yi Xing and Lan Lin and Paul J. Gadue},
journal = {Blood vessels, thrombosis \& hemostasis},
year = {2026},
month = aug,
doi = {10.1016/j.bvth.2026.100201},
url = {https://europepmc.org/article/PMC/PMC13717861},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - An iPSC model of thrombocytopenia-absent radius syndrome links aberrant splicing to impaired megakaryopoiesis
AU - Catriana C. Nations
AU - Jenea I. Adams
AU - Nicole Debruyne
AU - Xiuli Sim
AU - Hyun Sook Ahn
AU - C. J. Willett
AU - James Warland
AU - Cedric Ghevaert
AU - Kathleen Freson
AU - Giulia Pavani
AU - Deborah L. French
AU - Mortimer Poncz
AU - Yi Xing
AU - Lan Lin
AU - Paul J. Gadue
PY - 2026
DA - 2026/08/13
JO - Blood vessels, thrombosis & hemostasis
DO - 10.1016/j.bvth.2026.100201
UR - https://europepmc.org/article/PMC/PMC13717861
AB - Thrombocytopenia-absent radius (TAR) syndrome is a rare disease characterized by thrombocytopenia that results from the defective differentiation of megakaryocyte (MK) precursors. It is caused by mutations in the exon junction complex member RBM8A; however, it is not understood how the deficiency in this gene leads to a defect in megakaryopoiesis. Using induced pluripotent stem cell lines derived from patients with TAR syndrome and isogenic lines with corrected expression of RBM8A, we compared the phenotypes of derivative hematopoietic progenitor cells (HPCs) and MK. Although the generation of HPCs was similar between lines, the proliferation of TAR MK was significantly reduced. This was accompanied by precocious maturation, differential expression of platelet signaling pathways, and enhanced apoptosis. Despite enhanced size and markers of maturation of TAR MK, 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 and platelet degranulation, demonstrating lineage-specific defects. We also identified several candidate targets that could contribute 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 mature MK and platelets.
SN - 2950-3272
ER -