Pituitary resistance to thyroid hormone associated with a base mutation in the hormone-binding domain of the human 3, 5,3[prime]-triiodothyronine receptor-[beta]

Journal Article · Sat May 01 00:00:00 EDT 1993 · Journal of Clinical Endocrinology and Metabolism; (United States)

DOI:https://doi.org/10.1210/jc.76.5.1254· OSTI ID:6309863

Sasaki, Shigekazu; Nakamura, Hirotoshi; Tagami, Tetsuya; Miyoshi, Yohzi; Nogimori, Tsuyoshi; Mitsuma, Terunori; Imura, Hiroo ^[1]

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1. Kyoto Univ. School of Medicine, Aichi (Japan)

Point mutations in the human T[sub 3] receptor-[beta] (TR[beta]) gene causing single amino acid substitutions have been identified in several different kindred with generalized resistance to thyroid hormone. Until now, no study has been reported on the TR gene in cases of pituitary resistance (PRTH). In the present study, the authors analyzed the TR[beta] gene in a 30-yr-old Japanese female with PRTH. She exhibited clinical features of hyperthyroidism, elevated serum thyroid hormone levels accompanied by inappropriately increased secretion of TSH, mildly elevated basal metabolic rate, and increased urinary excretion of hydroxyproline. No pituitary tumor was detected. DNA fragments of exons 3-8 of the geonomic TR[beta] gene were generated by the polymerase chain reaction and analyzed by a single stranded conformation polymorphism method. Exon 7 of the patient's TR[beta] gene showed an abnormal band, suggesting the existence of mutation(s). By subcloning and sequencing the DNA, a point mutation was identified in one allele at nucleotide 1297 (C to T), which altered the 333rd amino acid, arginine, to tryptophan. Neither of her apparently normal parents had any mutations of the TR[beta] gene. In vitro translation products of the mutant TR[beta] gene showed remarkably decreased T[sub 3]-binding activity (K[sub a], 2.1 [times] 10[sup 8] M[sup [minus]1]; normal TR[beta] K[sub a], 1.1 [times] 10[sup 10] M[sup [minus]1]). Since the molecular defect detected in a patient with PRTH is similar to that seen in subjects with generalized resistance to thyroid hormone, both types of the syndrome may represent a continuous spectrum of the same etiological defect with variable tissue resistance to thyroid hormone.

• OSTI ID: 6309863
• Journal Information: Journal of Clinical Endocrinology and Metabolism; (United States), Vol. 76:5; ISSN 0021-972X
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ENDOCRINE DISEASES
GENE MUTATIONS
RECEPTORS
TRIIODOTHYRONINE
DNA BASE TRANSITIONS
DNA SEQUENCING
DNA-CLONING
PITUITARY GLAND
THYROID HORMONES
BODY
CLONING
DISEASES
DNA HYBRIDIZATION
ENDOCRINE GLANDS
GLANDS
HORMONES
HYBRIDIZATION
MEMBRANE PROTEINS
MUTATIONS
ORGANIC COMPOUNDS
ORGANS
PEPTIDE HORMONES
PROTEINS
STRUCTURAL CHEMICAL ANALYSIS
550400* - Genetics
551000 - Physiological Systems