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

Journal Article · Sun Oct 01 04:00:00 EDT 1995 · Journal of Clinical Endocrinology and Metabolism

DOI:https://doi.org/10.1210/jc.80.11.3239· OSTI ID:443619

Ozata, M; Suzuki, Satoru; Takeda, Teiji ^[1]

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1. Univ. of Toronto, Ontario (Canada); and others

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.

• OSTI ID: 443619
• Journal Information: Journal of Clinical Endocrinology and Metabolism, Journal Name: Journal of Clinical Endocrinology and Metabolism Journal Issue: 10 Vol. 80; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
BEHAVIOR
CODONS
DIAGNOSIS
DNA SEQUENCING
GENE MUTATIONS
GENES
GENETICS
MENTAL DISORDERS
MUTATION FREQUENCY
NUCLEOTIDES
PATIENTS
PHENOTYPE
PLASMIDS
POLYMERASE CHAIN REACTION
RECEPTORS
THYROID HORMONES