The relative expression of mutant and normal thyroid hormone receptor genes in patients with generalized resistance to thyroid hormone determined by estimation of their specific messenger ribonucleic acid products

Y. Hayashi, O. E. Janssen, Roy E Weiss, Y. Murata, H. Seo, S. Refetoff

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Generalized resistance to thyroid hormone (GRTH), is a syndrome of reduced tissue responsiveness to thyroid hormone. So far, mutations linked to GRTH have been only detected in the hormone-binding domain of the human thyroid hormone receptor (hTR)-β gene. Although there is no doubt that these mutations result in abnormal hTRs, there is a conspicuous lack of correlation between the severity of clinical manifestations and the degree of functional impairment of the mutant hTRs. In this work we examined whether variable expression of mutant genes relative to the normal genes could explain the observed discrepancies. The relative amounts of mutant and normal hTRβ and normal hTRα messenger RNAs in fibroblasts from normal subjects and those from individuals with GRTH were estimated by coamplification of their complementary DNA products. Heterozygous subjects with GRTH from two families manifesting differences in the severity of clinical manifestations expressed equally both normal and mutant hTRβ alleles. Furthermore, there was no compensatory increase in the expression of the normal hTRα gene in these individuals nor in fibroblasts from members of a third family with homozygous deletion of the hTRβ gene. In vitro treatment with thyroid hormone did not affect the results. It is concluded that the apparent discrepancies between the functional impairment of the mutant hTRs and the clinical manifestations of GRTH are not due to quantitative differences in the expression of the normal or mutant hTR genes but more likely to variations in the interactions of the mutant hTRs with the normal hTRβ, hTRα and nuclear stabilization factors.

Original languageEnglish (US)
Pages (from-to)64-69
Number of pages6
JournalJournal of Clinical Endocrinology and Metabolism
Volume76
Issue number1
DOIs
StatePublished - 1993
Externally publishedYes

Fingerprint

Thyroid Hormone Resistance Syndrome
Thyroid Hormone Receptors
Thyroid Hormones
Genes
RNA
Fibroblasts
Mutation
Stabilization
Complementary DNA
Alleles
Hormones
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

Cite this

@article{35db450c665248d9aeee6a294f75de8f,
title = "The relative expression of mutant and normal thyroid hormone receptor genes in patients with generalized resistance to thyroid hormone determined by estimation of their specific messenger ribonucleic acid products",
abstract = "Generalized resistance to thyroid hormone (GRTH), is a syndrome of reduced tissue responsiveness to thyroid hormone. So far, mutations linked to GRTH have been only detected in the hormone-binding domain of the human thyroid hormone receptor (hTR)-β gene. Although there is no doubt that these mutations result in abnormal hTRs, there is a conspicuous lack of correlation between the severity of clinical manifestations and the degree of functional impairment of the mutant hTRs. In this work we examined whether variable expression of mutant genes relative to the normal genes could explain the observed discrepancies. The relative amounts of mutant and normal hTRβ and normal hTRα messenger RNAs in fibroblasts from normal subjects and those from individuals with GRTH were estimated by coamplification of their complementary DNA products. Heterozygous subjects with GRTH from two families manifesting differences in the severity of clinical manifestations expressed equally both normal and mutant hTRβ alleles. Furthermore, there was no compensatory increase in the expression of the normal hTRα gene in these individuals nor in fibroblasts from members of a third family with homozygous deletion of the hTRβ gene. In vitro treatment with thyroid hormone did not affect the results. It is concluded that the apparent discrepancies between the functional impairment of the mutant hTRs and the clinical manifestations of GRTH are not due to quantitative differences in the expression of the normal or mutant hTR genes but more likely to variations in the interactions of the mutant hTRs with the normal hTRβ, hTRα and nuclear stabilization factors.",
author = "Y. Hayashi and Janssen, {O. E.} and Weiss, {Roy E} and Y. Murata and H. Seo and S. Refetoff",
year = "1993",
doi = "10.1210/jc.76.1.64",
language = "English (US)",
volume = "76",
pages = "64--69",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "1",

}

TY - JOUR

T1 - The relative expression of mutant and normal thyroid hormone receptor genes in patients with generalized resistance to thyroid hormone determined by estimation of their specific messenger ribonucleic acid products

AU - Hayashi, Y.

AU - Janssen, O. E.

AU - Weiss, Roy E

AU - Murata, Y.

AU - Seo, H.

AU - Refetoff, S.

PY - 1993

Y1 - 1993

N2 - Generalized resistance to thyroid hormone (GRTH), is a syndrome of reduced tissue responsiveness to thyroid hormone. So far, mutations linked to GRTH have been only detected in the hormone-binding domain of the human thyroid hormone receptor (hTR)-β gene. Although there is no doubt that these mutations result in abnormal hTRs, there is a conspicuous lack of correlation between the severity of clinical manifestations and the degree of functional impairment of the mutant hTRs. In this work we examined whether variable expression of mutant genes relative to the normal genes could explain the observed discrepancies. The relative amounts of mutant and normal hTRβ and normal hTRα messenger RNAs in fibroblasts from normal subjects and those from individuals with GRTH were estimated by coamplification of their complementary DNA products. Heterozygous subjects with GRTH from two families manifesting differences in the severity of clinical manifestations expressed equally both normal and mutant hTRβ alleles. Furthermore, there was no compensatory increase in the expression of the normal hTRα gene in these individuals nor in fibroblasts from members of a third family with homozygous deletion of the hTRβ gene. In vitro treatment with thyroid hormone did not affect the results. It is concluded that the apparent discrepancies between the functional impairment of the mutant hTRs and the clinical manifestations of GRTH are not due to quantitative differences in the expression of the normal or mutant hTR genes but more likely to variations in the interactions of the mutant hTRs with the normal hTRβ, hTRα and nuclear stabilization factors.

AB - Generalized resistance to thyroid hormone (GRTH), is a syndrome of reduced tissue responsiveness to thyroid hormone. So far, mutations linked to GRTH have been only detected in the hormone-binding domain of the human thyroid hormone receptor (hTR)-β gene. Although there is no doubt that these mutations result in abnormal hTRs, there is a conspicuous lack of correlation between the severity of clinical manifestations and the degree of functional impairment of the mutant hTRs. In this work we examined whether variable expression of mutant genes relative to the normal genes could explain the observed discrepancies. The relative amounts of mutant and normal hTRβ and normal hTRα messenger RNAs in fibroblasts from normal subjects and those from individuals with GRTH were estimated by coamplification of their complementary DNA products. Heterozygous subjects with GRTH from two families manifesting differences in the severity of clinical manifestations expressed equally both normal and mutant hTRβ alleles. Furthermore, there was no compensatory increase in the expression of the normal hTRα gene in these individuals nor in fibroblasts from members of a third family with homozygous deletion of the hTRβ gene. In vitro treatment with thyroid hormone did not affect the results. It is concluded that the apparent discrepancies between the functional impairment of the mutant hTRs and the clinical manifestations of GRTH are not due to quantitative differences in the expression of the normal or mutant hTR genes but more likely to variations in the interactions of the mutant hTRs with the normal hTRβ, hTRα and nuclear stabilization factors.

UR - http://www.scopus.com/inward/record.url?scp=0027469410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0027469410&partnerID=8YFLogxK

U2 - 10.1210/jc.76.1.64

DO - 10.1210/jc.76.1.64

M3 - Article

VL - 76

SP - 64

EP - 69

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 1

ER -