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JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol.86, no.9, pp.4468-4471, 2001 (SCI-Expanded)
We identified a new nonsense mutation of the TSH-beta subunit gene responsible for a severe isolated TSH deficiency in two children from the same consanguineous kindred. These affected children are homozygous for a C-to-T transition at nucleotide 654 of the TSH-beta subunit gene, leading to the conversion of a glutamine (CAG) to a premature stop codon (TAG) in the codon 49 (Q49X). The resulting nascent peptide does not contain the seat belt region (amino acid residues 88-105), a TSH-beta subunit region crucial for the dimerization with the alpha -subunit, and, hence, the correct secretion of the mature TSH heterodimer is hampered. Free T(3), free T(4) as well as basal TSH levels were extremely low in both affected individuals and, importantly, TRH stimulations failed to increase serum TSH, but not PRL, confirming isolated TSH deficiency. Using the new StyI endonuclease restriction site generated by the mutation, we confirmed that the affected children were homozygous for the Q49X TSH-beta mutation whereas their unaffected parents as well as their unaffected brother were heterozygous. Consequently, this isolated TSH deficiency follows an autosomal recessive mode of inheritance.