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Title: Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor {beta}1 gene

Abstract

Mutations in the gene encoding human thyroid hormone receptor {beta}(hTR{beta}) have been associated with generalized resistance to thyroid hormone (GRTH). This disorder is associated with significant behavoral abnormalities. We examined the hTR{beta} gene in a family with members who manifest inappropriately normal TSH, elevated free T{sub 4}, and free and total T{sub 3}. Sequence analysis showed a cytosine to thymine transition at nucleotide 1642 in one allele of the index patient`s genomic DNA. This altered proline to serine at codon 453. The resulting mutant receptor when expressed in vitro bound DNA with high affinity, but the T{sub 3} affinity of the receptor was impaired. The mutant TR demonstrated a dominant negative effect when cotransfected with two isoforms of wild-type receptor and also in the presence of TR variant {alpha}2 in COS-1 cells. Mutations of codon 453 occur more frequently than at other sites, and four different amino acid substitutions have been reported. Significant differences in phenotype occur among affected individuals, varying from normality to moderately severe GRTH. There is no clear correlation between K{sub a} or in vitro function of the mutant receptor, and phenotype. This study extends the association between GRTH and illness, and indicates that early diagnosis andmore » counseling are needed in families with TR{beta}1 abnormalities. 34 refs., 5 figs., 2 tabs.« less

Authors:
; ;  [1]
  1. Univ. of Toronto, Ontario (Canada) [and others
Publication Date:
OSTI Identifier:
443619
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Clinical Endocrinology and Metabolism; Journal Volume: 80; Journal Issue: 10; Other Information: PBD: Oct 1995
Country of Publication:
United States
Language:
English
Subject:
55 BIOLOGY AND MEDICINE, BASIC STUDIES; GENES; GENE MUTATIONS; DNA SEQUENCING; MUTATION FREQUENCY; RECEPTORS; THYROID HORMONES; PATIENTS; BEHAVIOR; PHENOTYPE; MENTAL DISORDERS; DIAGNOSIS; GENETICS; CODONS; AMINO ACIDS; NUCLEOTIDES; PLASMIDS; POLYMERASE CHAIN REACTION

Citation Formats

Ozata, M., Suzuki, Satoru, and Takeda, Teiji. Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor {beta}1 gene. United States: N. p., 1995. Web. doi:10.1210/jc.80.11.3239.
Ozata, M., Suzuki, Satoru, & Takeda, Teiji. Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor {beta}1 gene. United States. doi:10.1210/jc.80.11.3239.
Ozata, M., Suzuki, Satoru, and Takeda, Teiji. Sun . "Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor {beta}1 gene". United States. doi:10.1210/jc.80.11.3239.
@article{osti_443619,
title = {Functional analysis of a proline to serine mutation in codon 453 of the thyroid hormone receptor {beta}1 gene},
author = {Ozata, M. and Suzuki, Satoru and Takeda, Teiji},
abstractNote = {Mutations in the gene encoding human thyroid hormone receptor {beta}(hTR{beta}) have been associated with generalized resistance to thyroid hormone (GRTH). This disorder is associated with significant behavoral abnormalities. We examined the hTR{beta} gene in a family with members who manifest inappropriately normal TSH, elevated free T{sub 4}, and free and total T{sub 3}. Sequence analysis showed a cytosine to thymine transition at nucleotide 1642 in one allele of the index patient`s genomic DNA. This altered proline to serine at codon 453. The resulting mutant receptor when expressed in vitro bound DNA with high affinity, but the T{sub 3} affinity of the receptor was impaired. The mutant TR demonstrated a dominant negative effect when cotransfected with two isoforms of wild-type receptor and also in the presence of TR variant {alpha}2 in COS-1 cells. Mutations of codon 453 occur more frequently than at other sites, and four different amino acid substitutions have been reported. Significant differences in phenotype occur among affected individuals, varying from normality to moderately severe GRTH. There is no clear correlation between K{sub a} or in vitro function of the mutant receptor, and phenotype. This study extends the association between GRTH and illness, and indicates that early diagnosis and counseling are needed in families with TR{beta}1 abnormalities. 34 refs., 5 figs., 2 tabs.},
doi = {10.1210/jc.80.11.3239},
journal = {Journal of Clinical Endocrinology and Metabolism},
number = 10,
volume = 80,
place = {United States},
year = {Sun Oct 01 00:00:00 EDT 1995},
month = {Sun Oct 01 00:00:00 EDT 1995}
}