New autosomal recessive mutation of the TSH-beta subunit gene causing central isolated hypothyroidism

We identified a new nonsense mutation of the TSH-beta subunit gene responsi ble for a severe isolated TSH deficiency in two children from the same cons anguineous kindred. These affected children are homozygous for a C-to-T tra nsition at nucleotide 654 of the TSH-beta subunit gene, leading to the conv ersion 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 regio n (amino acid residues 88-105), a TSH-beta subunit region crucial for the d imerization with the alpha -subunit, and, hence, the correct secretion of t he 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 is olated TSH deficiency. Using the new StyI endonuclease restriction site gen erated by the mutation, we confirmed that the affected children were homozy gous for the Q49X TSH-beta mutation whereas their unaffected parents as wel l as their unaffected brother were heterozygous. Consequently, this isolate d TSH deficiency follows an autosomal recessive mode of inheritance.