Pierpont syndrome is a rare disorder characterized mainly by global developmental delay, unusual facial features, altered fat distribution in the limbs, and hearing loss. A specific mutation (p.Tyr446Cys) in TBL1XR1, encoding a WD40 repeat-containing protein which is a component of the SMRT/NCoR corepressor, has been reported as the genetic cause of Pierpont syndrome. Here we used CRISPR-cas9 technology to generate a mutant mouse with the Y446C mutation in Tbl1xr1 which is also present in Pierpont syndrome. Several aspects of the phenotype were studied in the mutant mice: growth, body composition, hearing, motor behavior, thyroid hormone state and lipid and glucose metabolism. The mutant mice (Tbl1xr1Y446C/Y446C) displayed delayed growth, altered body composition with increased relative lean mass, and impaired hearing. Expression of several genes involved in fatty acid metabolism differed in white adipose tissue, but not in liver or muscle of mutant mice compared to wild type mice (Tbl1xr1+/+). No difference in thyroid hormone plasma concentrations was observed. Tbl1xr1Y446C/Y446C mice can be used as a model for distinct features of Pierpont syndrome which will enable future studies on the pathogenic mechanisms underlying the various phenotypic characteristics.

WD40 repeat-containing proteins play a key role in many cellular functions including signal transduction, protein degradation, and apoptosis. The WD40 domain is highly conserved, and its typical structure is a β-propeller consisting of 4-8 blades which probably serves as a scaffold for protein-protein interaction. Some WD40 repeat-containing proteins form part of the corepressor complex of nuclear hormone receptors, a family of ligand-dependent transcription factors that play a central role in the regulation of gene transcription. This explains their involvement in endocrine physiology and pathology. In the present review, we first touch upon the structure of WD40 repeat-containing proteins. Next, we describe our current understanding of the role of WD40 domain containing proteins in nuclear receptor signaling e.g. as corepressor or coactivator. In the final part of this review, we focus on WD40 domain containing proteins that are associated with endocrine pathologies. These pathologies vary from isolated dysfunction of one endocrine axis, e.g., congenital isolated central hypothyroidism, to more complex congenital syndromes comprising endocrine phenotypes, such as the Triple-A syndrome.

TBL1XR1 is a WD40 repeat-containing protein and part of the corepressor complex SMRT/NCoR that binds to the thyroid hormone receptor. We recently described a mutation in TBL1XR1 in patients with Pierpont syndrome. A mouse model bearing this Tbl1xr1 mutation (Tbl1xr1Y446C/Y446C) displays several aspects of the Pierpont phenotype. Although serum thyroid hormone (TH) concentrations were unremarkable in these mice, tissue TH action might be affected due to the role of TBL1XR1 in the SMRT/NCoR corepressor complex. The aim of the present study was to evaluate tissue TH metabolism and action in a variety of tissues of Tbl1xr1Y446C/Y446C mice. We studied the expression of genes involved in TH metabolism and action in tissues of naïve Tbl1xr1Y446C/Y446C mice and wild type (WT) mice. In addition, we measured deiodinase activity in liver (Dio1 and Dio3), kidney (Dio1 and Dio3) and BAT (Dio2). No striking differences were observed in liver, hypothalamus, muscle and BAT between Tbl1xr1Y446C/Y446C and WT mice. Pituitary TRα1 mRNA expression was lower in Tbl1xr1Y446C/Y446C mice compared to WT, while mRNA expression of Tshβ and the positively T3-regulated gene Nmb were significantly increased in mutant mice. Interestingly, Mct8 expression was markedly higher in WAT and kidney of mutants resulting in (subtle) changes in T3 regulated gene expression in both WAT and kidney. In conclusion, mice harboring a mutation in TBL1XR1 display minor changes in cellular thyroid hormone metabolism and action. TH transport via MCT8 might be affected as expression is increased in WAT and kidney. The mechanisms involved need to be clarified.