An animal model for Pierpont syndrome: a mouse bearing the Tbl1xr1 Y446C/Y446C mutation

Abstract

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.

The role of transducin β-like 1 X-linked receptor 1 (TBL1XR1) in thyroid hormone metabolism and action in mice

“…Both TBL1XR1 and TBL1X are being part of the NCoR/SMRT corepressor complex and have overlapping functions, it is reasonable to assume that a defective TBL1XR1 may have an effect on TH signaling via the affected SMRT/NCoR corepressor complex as observed in patients with mutations in TBL1X. Indeed, we observed changes in some T3-responsive genes in white adipose tissue of Tbl1xr1 Y446C/Y446C mice compared to the WT ( 6 ).…”

“…Tbl1xr1 Y446C/Y446C mice were generated using CRISPR-Cas9 technology as previously described ( 6 ). Mice at the age of 12 weeks were sacrificed by exsanguination.…”

“…Total RNA from the hypothalamus, pituitary, liver, kidney, WAT, BAT and gastrocnemius muscle was isolated as previously described ( 6 ). Total RNA from HepG2 cells was isolated using the High Pure RNA isolation kit (Roche).…”

“…To understand the functional consequences of the mutation at the tissue level, we developed an animal model bearing the Tbl1xr1 Y446C mutation using CRISPR-Cas9 technology. The mice displayed delayed growth, changed body composition and impaired hearing ( 6 ). As in humans with Pierpont syndrome, also in the animal model, no differences in serum thyroxine (T4), triiodothyronine (T3) and thyroid-stimulating-hormone (TSH) concentrations were observed between Tbl1xr1 Y446C/Y446C and wild type (WT) mice ( 6 ).…”

“…The mice displayed delayed growth, changed body composition and impaired hearing ( 6 ). As in humans with Pierpont syndrome, also in the animal model, no differences in serum thyroxine (T4), triiodothyronine (T3) and thyroid-stimulating-hormone (TSH) concentrations were observed between Tbl1xr1 Y446C/Y446C and wild type (WT) mice ( 6 ).…”