Functional consequences of a similar mutation in the co-repressor components TBL1XR1 and TBL1X – focus on thyroid hormone signaling

The WD40 repeat-containing proteins TBL1XR1 and its homologue TBL1X form part of the NCoR1/SMRT corepressor complex. This complex can regulate gene expression through binding to multiple nuclear receptors including the thyroid hormone receptor (TR). Our group reported a specific single heterozygous missense variant, Y446C, in TBL1XR1 as the genetic cause of Pierpont syndrome in several patients with this condition. Pierpont syndrome is a rare disorder mainly characterized by global developmental delay, unusual facial features, altered fat distribution in the limbs and hearing loss. Moreover, we identified the variant Y509C in TBL1X in a family with the combination of isolated central congenital hypothyroidism and impaired hearing. Strikingly, it appeared that the TBL1XR1 Y446C variant and the TBL1X Y509C variant are located in the identical location of the WD40 domain. The marked differences in phenotype between individuals with the Y446C mutation in TBL1XR1 and Y509C in TBL1X suggest that corepressor complexes containing TBL1X vs TBL1XR1 have at least partly different activities or are active in different contexts. In this thesis, we used two mouse models carrying the Tbl1xr1^Y446C/Y446C variant and Tbl1x ^Y459C variant, respectively, as well as multiple cell lines to study the function of TBL1XR1 and TBL1X at the tissue level mainly focusing on thyroid hormone (TH) signaling.