Germline mutation in Cbl proto-oncogene B is associated with inherited thrombocytopenia and predisposes megakaryocytes to ferroptosis.

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.