Biochimica et biophysica acta. Molecular basis of disease · 2025
Germline mutation in Cbl proto-oncogene B is associated with inherited thrombocytopenia and predisposes megakaryocytes to ferroptosis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Xiao Xiang, Xie Rongli, Zhang Yang, Yin Yafei, Chen Yongheng, Sun Nannan, Cheng Zhao, Zhang Guangsen
Аннотация
BACKGROUND: Inherited thrombocytopenias (ITs) are a group of heterogeneous diseases characterized by low platelet counts and bleeding diathesis. ITs are primarily caused by mutations in genes involved in megakaryocyte differentiation, maturation and platelet release. To date, ITs encompass 45 disorders with different degrees of variability in the prognosis.
OBJECTIVES: We aimed to identify the predisposing gene in members of a family with inherited thrombocytopenia and elucidate its etiology and pathogenesis.
METHODS: Whole exome sequencing was performed using samples from the proband and the proband's family members. Sanger sequencing validated the mutation. A cellular model of the transmutated gene was established using a human megakaryocytic cell line. The influence of potential pathogenic mutation on T-cell functional population and megakaryocyte ferroptosis was evaluated.
RESULTS: Through whole exome sequencing of the proband and his family members (n = 4) we identified a potential pathologic c.2213A > G mutation (p.Asn738Ser) in the CBLB gene. The patients harboring the c.2213A > G mutant displayed an increased abundance of Th2/Tc2 cells. In lentivirus-transformed CMK cells with the c.2213A > G mutation, ferroptosis was significantly increased.
CONCLUSION: c.2213A > G mutation on the CBLB gene causes a new type of inherited thrombocytopenia, and the potential pathogenesis involves an imbalance in cellular immunity and excessive ferroptosis of megakaryocytes.
OBJECTIVES: We aimed to identify the predisposing gene in members of a family with inherited thrombocytopenia and elucidate its etiology and pathogenesis.
METHODS: Whole exome sequencing was performed using samples from the proband and the proband's family members. Sanger sequencing validated the mutation. A cellular model of the transmutated gene was established using a human megakaryocytic cell line. The influence of potential pathogenic mutation on T-cell functional population and megakaryocyte ferroptosis was evaluated.
RESULTS: Through whole exome sequencing of the proband and his family members (n = 4) we identified a potential pathologic c.2213A > G mutation (p.Asn738Ser) in the CBLB gene. The patients harboring the c.2213A > G mutant displayed an increased abundance of Th2/Tc2 cells. In lentivirus-transformed CMK cells with the c.2213A > G mutation, ferroptosis was significantly increased.
CONCLUSION: c.2213A > G mutation on the CBLB gene causes a new type of inherited thrombocytopenia, and the potential pathogenesis involves an imbalance in cellular immunity and excessive ferroptosis of megakaryocytes.