Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia.

Details

Serval ID
serval:BIB_5738
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia.
Journal
Journal of Clinical Endocrinology and Metabolism
Author(s)
Tonacchera M., Van Sande J., Cetani F., Swillens S., Schvartz C., Winiszewski P., Portmann L., Dumont J.E., Vassart G., Parma J.
ISSN
0021-972X
Publication state
Published
Issued date
1996
Volume
81
Number
2
Pages
547-554
Language
english
Notes
Publication types: Journal Article
Abstract
We report three unrelated families in which hyperthyroidism associated with thyroid hyperplasia was transmitted in an autosomal dominant fashion, in the absence of signs of autoimmunity. Exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from DNA of peripheral leukocytes. In one family, a C to A transversion resulted in an S505R substitution in the third transmembrane segment; in the second, an A to T transversion caused a N650Y substitution in the sixth transmembrane segment; and in the third family, an A to G transition resulted in an N670S substitution in the seventh transmembrane segment. When expressed by transfection in COS-7 cells, each mutated receptor displayed an increase in constitutive stimulation of cAMP production; no effect on basal accumulation of inositol phosphates (IP) could be detected. In binding studies, cells transfected with wild-type or mutated receptors showed similar levels of expression, with the mutated receptors displaying similar or slightly increased affinity for bovine TSH (bTSH) binding. Cells transfected with S505R and N650Y mutants showed a similar cAMP maximal TSH-stimulated accumulation over the cells transfected with the wild type, whereas N670S transfectants showed a blunted response with an increase in EC50. A higher IP response to 100 mU/mL bTSH over that obtained with the wild-type receptor was obtained in cells transfected with N650Y; in contrast, cells transfected with S505R showed a blunted IP production (50% less), and the N670S mutant completely lost the ability to stimulate IP accumulation in response to bTSH. The differential effects of individual mutations on stimulation by bTSH of cAMP or IP accumulation suggest that individual mutant receptors may achieve different active conformations with selective abilities to couple to Gs alpha and to Gq alpha.
Keywords
Amino Acid Sequence, Base Sequence, Cyclic AMP/biosynthesis, Female, Humans, Hyperplasia/genetics, Inositol Phosphates/metabolism, Male, Molecular Sequence Data, Mutation, Pedigree, Polymerase Chain Reaction, Receptors, Thyrotropin/genetics, Sequence Analysis, DNA, Thyroid Gland/pathology, Thyrotropin/metabolism, Thyrotropin/pharmacology, Transfection
Pubmed
Web of science
Create date
19/11/2007 13:42
Last modification date
20/08/2019 15:11
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