A Novel Thyrotropin Receptor Mutation in an Infant with Severe Thyrotoxicosis

Abstract

An infant girl was born at 37 weeks gestation and found to be clinically thyrotoxic at 9 months of age. Thyroid autoantibodies were negative, and thyroid function failed to normalize with medical treatment. The patient underwent a total thyroidectomy. DNA obtained from her thyroid gland and leukocytes was analyzed for thyrotropin receptor (TSHR) mutations using single strand conformation polymorphism and direct sequencing. A mobility shift of polymerase chain reaction (PCR)-amplified DNA was detected on single strand conformation polymorphism gel. Direct sequencing identified a novel point mutation in the fifth transmembrane domain of the TSH receptor at codon 597 (GTC to CTC), resulting in the amino acid substitution of leucine for valine. The mutation was heterozygous and germline, and was not identified in DNA from either of her parents. Expression of the V597L mutant is transiently transfected COS 7 cells displayed increased constitutive cyclic adenosine monophosphate (cAMP) production compared with the wild-type receptor. The mutant is expressed at very low levels on the surface of COS cells, and its response to TSH is marginal.

A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism

“…The presence of the V597F mutant on the plasmatic membrane is con®rmed by the conserved response to TSH stimulation. The same codon was recently found mutated with a different substitution (V597L) in one infant with severe thyrotoxicosis (8). Functional experiments of the V597L TSHR mutant showed a dramatic increase in ligand-independent receptor activity associated with the severe impairment of membrane targeting, leading to a diminished response to TSH stimulation.…”

“…In fact, the V597L mutation was found in one sporadic case with infantile onset (at 9 months of age) of severe thyrotoxic features (8), whereas V597F is associated with a childhood to juvenile onset of thyrotoxic features. Germline mutations causing dramatic increases in TSHR constitutive activity causing severe thyrotoxicosis since early infancy (or even congenital) (3±9) may be associated with intellectual impairment and craniosynostosis in later years (22), and familial vertical transmission may become unlikely.…”

A sequence variation in the MOG gene is involved in multiple sclerosis susceptibility in Italy

“…There are several instances of diseases in which V/L variations in transmembrane domains (for example in proteins encoded by CFTR, ABC7, PSEN1, TSHR, ACHR, VKORC1) were shown to be causative mutations (references [35][36][37][38][39] and www.genet.sickkids.on.ca/cftr).…”

Sporadic Congenital Hyperthyroidism due to a Germline Mutation in the Thyrotropin Receptor Gene (Leu 512 Gln) in a Japanese Patient

“…These mutant regions of TSHR which are the molecular basis for nonautoimmune hyperthyroidism overlap with those of toxic thyroid nodules, suggesting the same mechanism of constitutive activation of TSHR by permanent activation of the cAMP cascade that stimulates the growth and function of thyrocytes. De novo activating TSHR germline mutations have been reported in 9 cases as the cause of sporadic congenital nonautoimmune hyperthyroidism [3][4][5][6][7][8][9][10][11]. The clinical features of sporadic nonautoimmune hyperthyroidism are the earlier onset of thyrotoxicosis and more severe thyrotoxicosis, which is difficult to control with antithyroid drug therapy, than that of familial cases [12].…”