A novel mechanism for isolated central hypothyroidism: Inactivating mutations in the thyrotropin-releasing hormone receptor gene

• Published in: The journal of clinical endocrinology and metabolism Vol. 82; no. 5; pp. 1561 - 1565
• Main Authors: COLLU, R, TANG, J, VAN VLIET, G, CASTAGNE, J, LAGACE, G, MASSON, N, HUOT, C, DEAL, C, DELVIN, E, FACCENDA, E, EIDNE, K. A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.05.1997
• Subjects: Biological and medical sciences; Cell Line; Child; DNA - analysis; DNA - chemistry; Endocrinopathies; Haplotypes; Humans; Hypothyroidism - genetics; Male; Medical sciences; Mutation; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Pedigree; Prolactin - secretion; Receptors, Thyrotropin-Releasing Hormone - genetics; Sequence Analysis, DNA; Thyroid. Thyroid axis (diseases); Thyrotropin - secretion; Thyrotropin-Releasing Hormone; Endocrinopathy; Human; Pathogenesis; Peptide hormone; Thyroid diseases; TSH; Glycoprotein hormone; Hypothyroidism; Hypothalamic hormone; Case study; TSH-RH; Adenohypophyseal hormone; Gene; Genetics; Mutation; Hormone releasing factor; Child; Hormonal receptor
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.82.5.1561

Isolated central hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder. We report a boy in whom isolated central hypothyroidism was diagnosed at 9 yr of age. Complete absence of TSH and PRL responses to TRH led us to speculate that he had an inactivating mutation of the TRH receptor gene. The patients' genomic DNA was isolated, and the entire coding region of the TRH receptor was amplified by the PCR and sequenced directly. Confirmation of the mutations and haplotyping of the family was performed using restriction enzymes. The biological activity of the wild-type and mutated TRH receptors was verified by evaluating the binding of labeled TRH and stimulation by TRH of total inositol phosphate accumulation in transfected HEK-293 and COS-1 cells. The patient was found to be a compound heterozygote, having inherited a different mutated allele from each of the parents; both mutations were in the 5'-part of the gene. Mutated receptors were unable to bind TRH and to activate total inositol phosphate accumulation. Our report is the first description of naturally occurring inactivating mutations of a G protein-coupled receptor linked to the phospholipase C second messenger pathway. The prevalence and phenotypic spectrum of TRH receptor mutations in isolated central hypothyroidism remain to be established.