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New Autosomal Recessive Mutation of the TSH-ß Subunit Gene Causing Central Isolated Hypothyroidism

Divisions of Pediatric Endocrinology (J.-M.V., J.D., G.G., P.E.M.) and Molecular Human Genetic (S.G.), University Children’s Hospital, 3010 Bern, Switzerland; and Dokuz Eylül Faculty of Medicine (A.B., P.C.), 35340 Izmir, Turkey

Address all correspondence and requests for reprints to: Prof. Dr. Primus E. Mullis, Division of Pediatric Endocrinology, University Children’s Hospital, CH-3010 Bern, Switzerland. E-mail: primus.mullis{at}insel.ch

Abstract

We identified a new nonsense mutation of the TSH-ß 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-ß 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-ß subunit region crucial for the dimerization with the -subunit, and, hence, the correct secretion of the mature TSH heterodimer is hampered. Free T₃, free T₄ 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-ß 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.

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