Patients with mutations of the THRA gene exhibit erythroid disorders. The molecular pathogenesis underlying erythroid abnormalities is poorly understood. Our recent studies have elucidated molecular mechanisms by which TRalpha1 mutants caused erythroid disorders in patients with mutations of THRA gene. In 2017-2018, we further studied how the nuclear receptor corepressor (NCOR1) regulated the dominant negative activity of mutated TRalpha1 in patients by using mouse models. We crossed Thra1PV/+ mice with mice expressing a mutant Ncor1 allele (NCOR1delataID; Ncor1deltaID mice) that cannot recruit TRalpha1PV mutant. The expression of NCOR1deltaID ameliorated abnormalities in the peripheral blood indices, and corrected the defective differentiation potential of progenitors in the erythroid lineage. The detective terminal erythropoiesis of lineage-negative bone marrow cells of Thra1PV/+ mice was rescued by the expression of NCOR1deltaID. De-repression of key erythroid genes in Thra1PV/+ Ncor1deltaID/deltaID mice led to partial rescue of terminal erythroid differentiation. These results indicate that the inability of TRalpha1PV to recruit NCOR1deltaID to form a repressor complex relieved the deleterious actions of TRalpha1 mutants in vivo. NCOR1 is a critical novel regulator underpining the pathogenesis of erythroid abnormalities caused by TRalpha1 mutants. Thus, NCOR1 is a potential target for the treatment of erythroid disorders in patients with mutations of the THRA gene.
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