Three novel mutations of thyroid hormone receptor {beta} gene in unrelated patients with resistance to thyroid hormone: Two mutations of the same codon (H435L and H435Q) produce separate subtypes of resistance

Journal Article · Fri Dec 01 04:00:00 EST 1995 · Journal of Clinical Endocrinology and Metabolism

DOI:https://doi.org/10.1210/jc.80.12.3613· OSTI ID:391041

Tsukaguchi, Hiroyasu; Yoshimasa, Yasunao; Fujimoto, Kazumitsu ^[1]

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1. Osaka Medical College, Takatsuki, Osaka (Japan); and others

We report three novel mutations of the thyroid hormone receptor {beta} (TR {beta}) gene in three unrelated Japanese patients with resistance to thyroid hormone (RTH). Patients A and B exhibited generalized resistance phenotype, while patient C displayed more pituitary-selective unresponsiveness. Direct sequencing of TR {beta} gene exon 10 disclosed novel point mutations in all three patients. A Phe to Ile (TTC{r_arrow}ATC) substitution at codon 451, a His to Leu (CAT{r_arrow}CTT) substitution at codon 435, and a His to Gln (CAT{r_arrow}CAA) substitution at codon 435 were identified in patients A, B, and C, respectively. Sequencing of TR {beta} gene exons 5-9 as well as TR {alpha} gene exons 4-9 failed to detect any additional mutations. All three patients were heterozygous for respective mutations. The unaffected parents of patients A and B, having normal thyroid function, possessed no mutations of TR {beta} gene exon 10, indicating that the F451I and H435L mutations occurred de novo. The F451I mutation is located near the most frequent mutation site in the ligand 2 subdomain. The identical codon mutations H435L and H435Q, which lie at the extreme carboxyl-terminus of the dimerization subdomain near the 9th heptad, were found in clinically different subtypes of RTH: patient B with generalized resistance and patient C with pituitary-selective resistance, respectively. The mutations broaden the growing catalogue of the TR {beta} gene mutations that could cause different phenotypes, despite the defects at the same codon. 21 refs., 1 fig., 3 tabs.

• OSTI ID: 391041
• Journal Information: Journal of Clinical Endocrinology and Metabolism, Journal Name: Journal of Clinical Endocrinology and Metabolism Journal Issue: 12 Vol. 80; ISSN JCEMAZ; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACIDS
CODONS
DNA SEQUENCING
EXONS
GENE MUTATIONS
GENES
JAPAN
LIGANDS
METABOLIC DISEASES
PATIENTS
PHENOTYPE
RECEPTORS
STRUCTURE-ACTIVITY RELATIONSHIPS
THYROID HORMONES