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A Novel Mechanism for Isolated Central Hypothyroidism: Inactivating Mutations in the Thyrotropin-Releasing Hormone Receptor Gene¹

Department of Pediatrics and the Research Unit on Biology of Reproduction and Development (R.C., J.T., J.C., G.L., N.M., C.H., C.D., G.V.V.), and Department of Biochemistry (E.D.), Sainte-Justine Hospital, University of Montreal, Montreal, Canada H3T 1C5; and the Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology (E.F., K.A.E.), Edinburgh, United Kingdom

Address all correspondence and requests for reprints to: Dr. Robert Collu, Research Center, Hôpital Sainte-Justine, 3175 côte Sainte-Catherine, Montreal, Quebec, Canada H3T 1C5. ). E-mail: Collu{at}justine.umontreal.ca

Isolated central hypothyroidism, characterized by insufficient TSH secretion resulting in low levels of thyroid hormones, is a rare disorder. We report a boy in whom isolated central hypothyroidism was diagnosed at 9 yr of age. Complete absence of TSH and PRL responses to TRH led us to speculate that he had an inactivating mutation of the TRH receptor gene. The patients’ genomic DNA was isolated, and the entire coding region of the TRH receptor was amplified by the PCR and sequenced directly. Confirmation of the mutations and haplotyping of the family was performed using restriction enzymes. The biological activity of the wild-type and mutated TRH receptors was verified by evaluating the binding of labeled TRH and stimulation by TRH of total inositol phosphate accumulation in transfected HEK-293 and COS-1 cells. The patient was found to be a compound heterozygote, having inherited a different mutated allele from each of the parents; both mutations were in the 5'-part of the gene. Mutated receptors were unable to bind TRH and to activate total inositol phosphate accumulation. Our report is the first description of naturally occurring inactivating mutations of a G protein-coupled receptor linked to the phospholipase C second messenger pathway. The prevalence and phenotypic spectrum of TRH receptor mutations in isolated central hypothyroidism remain to be established.

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