Thyroid Research Thyroid Research Archive Hypothyroidism

Some patients with subclinical hypothyroidism have mutations in the gene for the thyrotropin receptor

(November 2002)

The background of the study. Subclinical hypothyroidism (high serum thyrotropin [TSH] but normal serum thyroid hormone concentrations) is common, and is usually caused by autoimmune thyroid disease. This study was done to determine if patients with subclinical hypothyroidism who had no evidence of autoimmune thyroid disease might have mutations in the gene for the TSH receptor that reduced the activity of the receptor.

How the study was done. The study subjects were 10 patients (age range, 23 days to 25 years) with subclinical hypothyroidism and their parents and siblings. The patients' initial serum TSH concentrations ranged from 6.6 to 46.0 mU/L; all had normal serum concentrations of free thyroxine and antithyroid peroxidase, antithyroglobulin, and anti-TSH receptor antibodies. Ultrasonography revealed thyroid hypoplasia in two patients and a normal thyroid gland in eight patients.

DNA was extracted from peripheral blood leukocytes, and the structure of the gene for the TSH receptor was determined. The mutations found in the patients were introduced into cells to determine the effect of the mutation on the activity of the receptor, as compared with the activity of the normal TSH receptor.

The results of the study. Five different mutations in the TSH-receptor gene were detected in 4 of the 10 patients. A parent or sibling of most of the patients had the same mutation, and they also had high serum TSH concentrations. Fewer TSH receptors were detected on cells carrying the mutated genes as compared with cells carrying the normal gene.

The conclusions of the study. Mutations in the gene for the TSH receptor gene can cause subclinical hypothyroidism.

The original article. Alberti L, Proverbio MC, Costagliola S, Romoli R, Boldrighini B, Vigone MC, Weber G, Chiumello G, Beck-Peccoz P, Persani L. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab 2002;87:2549-55.