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Subclinical hypothyroidism of chronic autoimmune thyroiditis must be distinguished from the rare condition of thyroid resistance to TSH in which variable degrees of congenital insensitivity of the thyroid to a biologically active TSH molecule are present. We studied 42 subjects with slight to moderate elevations of circulating TSH and normal free thyroid hormone levels in whom the diagnosis of autoimmune thyroid disease had been excluded using the best of the currently available laboratory and instrumental techniques. In three families (A, B, and C), which included 8 of the 42 cases, other members besides the propositus were found to have isolated hyperthyrotropinemia. The entire coding regions of the TSH receptor (TSHr) gene were sequenced, and TSHr mutations were found in five subjects from families A and B. No mutations were identified in the two members of family C, in one member of family A, and in the 34 remaining cases of isolated hyperthyrotropinemia. A previously described P162A mutation was found in the proband (homozygous state), the son, and the mother of family A (both in the heterozygous state). A new inactivating heterozygous mutation was found in the proband and the mother of family B and consisted of the substitution of a leucine in place of a highly conserved proline at position 252 (L252P) in the extracellular portion of the TSHr. After transfection in COS-7 cells, the mutant L252P displayed a low expression at the cell surface and a reduced response to bovine TSH in terms of cAMP production. A structural defect of the mutant TSHr protein was probably responsible for the poor routing of the receptor to the cell membrane. In conclusion, in two of three families, but in none of 34 sporadic cases of isolated hyperthyrotropinemia, inactivating mutations of the TSHr were identified. The question of whether the latter cases represent subtle forms of autoimmune thyroiditis or might bear as yet unidentified genetic defects remains a matter of future studies.

Low Prevalence of Thyrotropin Receptor Mutations in a Large Series of Subjects with Sporadic and Familial Nonautoimmune Subclinical Hypothyroidism