Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.

Abstract

Thyroid hormone resistance (THR) is primarily an autosomal dominant inherited disease characterized by resistance of pituitary and peripheral tissues to the action of thyroid hormone. We investigated whether the heterogeneous phenotypic features that occur not only among kindreds but also within the same kindred might be due to the expression of differing ratios of mutant and normal receptors in tissues. Using an allele-specific primer extension method, we determined the relative expression of normal and mutant mRNAs from the fibroblasts of affected and unaffected members of two kindreds with TRH: A-H and N-N. While two affected members of A-H, as expected, had nearly equal amounts of normal and mutant hTR(3 mRNA, two other members had mutant mRNA levels that accounted for at least 70% of the hTR# mRNA. Phenotypic variability within and between kindreds with generalized resistance to thyroid hormone GRTH may be due to this differential expression of the mutant and wild type mRNA. Furthermore, when several clinical parameters of THR were compared in several affected members from two kindreds with GRTH, we found that two cases in one kindred exhibited a high mutant-tonormal hTR68 ratio and had considerably more bone resistance during their development. In certain kindreds with THR, differing ratios of normal and mutant hTR receptors may be age and growth related and may account for the reported attenuation of phenotypic symptoms with age. (J. Clin. Invest. 1993.

Hormone binding induces rapid proteasome-mediated degradation of thyroid hormone receptors

“…The only two studies that address this issue reported conflicting results (28,29). In the first study, the severity of growth delay in a kindred with RTH correlated with the increased ratio of mutant to wild-type TR␤1 mRNA in fibroblasts (28). However, in a second study, no correlation was found between the relative ratios of mutant and normal TR␤1 mRNA in fibroblasts and the clinical phenotype of RTH patients (29).…”

“…One of the unresolved issues in understanding the molecular basis of RTH has related to the relative levels of mutant to wild-type TR␤1 protein to produce a clinical phenotype in different organs. The only two studies that address this issue reported conflicting results (28,29). In the first study, the severity of growth delay in a kindred with RTH correlated with the increased ratio of mutant to wild-type TR␤1 mRNA in fibroblasts (28).…”

Syndromes of Reduced Sensitivity to Thyroid Hormone

“…This phenotypic variation can occur across families [38] and within the same family [57]. Finding differences in the relative expression level of the mutant relative to the normal TRβ allele has not been consistent [48,58]. Genetic variability of factors other than TRβ may modulate the phenotype of RTH.…”

Metabolism of thyroid hormones in cultured cardiac fibroblasts of neonatal rats

“…The inhibitory effect of T4 on cardiac collagen synthesis has been observed in rat, mouse and dog (Edgren et al 1976, Bonnin et al 1983, Yao & Eghbali 1992a,b, Kim et al 1996, Klein et al 1996, and it has been postulated that this negatively affects the supporting properties of the myocardial connective tissue (Edgren et al 1976). Fibroblasts from human skin biopsies express a thyroid hormone receptor (Mixson et al 1993), and it is possible that, besides the well-investigated collagen genes, novel thyroid hormone-responsive genes will be identified in (cardiac) fibroblasts. Indeed, the recently discovered ZAKI-4 gene, with an as yet unknown function, was identified in fibroblasts and found to be transcribed in heart and several other organs (Miyazaki et al 1996a,b).…”