Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis

Abstract

Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor β (THRB) have been identified in TD, the mutational spectrum of THRB and phenotype-genotype correlations have not been fully elucidated. In this study, we aimed to find mutations of THRB, examine the functions of these mutations, and attempt to elucidate the relationship between THRB and TD. Thus, we screened the exons of THRB in 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse-transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy-ori cell line) to examine the impact of THRB mutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified in THRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na /I symporter (NIS) were decreased in a time-dependent manner in mutant THRB compared with the wild type. To our knowledge, this is the first study to document the prevalence of THRB mutations and the genotype-phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for genetic THRB defects and disease mechanisms in TD.

Molecular defects in thyroid dysgenesis

“…A paper by Zhou et al highlighted two THRB missense mutations screening a cohort of 280 patients with TD and 200 normal subjects . The thyroid hormone receptor β (THRB), indeed, possesses a ligand‐binding domain (LBD) in the C‐terminus through which it interacts with the T3 thyroid hormone.…”

“…The thyroid hormone receptor β (THRB), indeed, possesses a ligand‐binding domain (LBD) in the C‐terminus through which it interacts with the T3 thyroid hormone. Patients harboring THRB mutations develops TD, with or without an ectopic lingual thyroid . Functional characterization the THRB C36Y mutation revealed changes in cell morphology that inhibited the human thyroid cell line Nthy‐ori 3‐1 proliferation, promoting apoptosis …”

DUOX2 and DUOXA2 Variants Confer Susceptibility to Thyroid Dysgenesis and Gland-in-situ With Congenital Hypothyroidism

“…Dyshormonogenesis is often due to genetic defects in important enzymes in thyroid hormone synthesis: iodine organification disorder (TPO, DUOX2, DUOXA2, and SLC26A4); thyroglobulin synthesis or transport defect (TG); iodine transport defect (SLC5A5); and iodotyrosine deiodinase deficiency (IYD) (17)(18)(19)(20). In addition, a very small proportion of CH children are severely resistant to thyroid hormones due to variants in THRB (21). Although genetic variants of candidate genes are involved in thyroid hormone synthesis and TSHR and intersect with genes associated with both TD and dyshormonogenesis (19,22), the genetic basis of GIS remains poorly understood.…”

Expanding the phenotype of THRB: a range of macular dystrophies as the major clinical manifestations in patients with a dominant splicing variant

“…Authors suggest that TRβ1, the predominant TRβ isoform at mature ages, may have a role in the survival of both cone photoreceptors and retinal pigment epithelium cells (Ng et al, 2023), as described in other retinal degeneration models (Ma et al, 2014;Ma et al, 2017;Ma et al, 2022), and now in the IRD patients of our cohort. Of note, only two putatively pathogenic variants have been identified in the TRβ1 N-terminal domain in patients with congenital hypothyroidism and thyroid dysgenesis (Zhou et al, 2018). However, the young age of these patients, the lack of an ophthalmologic evaluation, and the VUS status of these variants hampered the proper establishment of genotype-phenotype correlations.…”