Functional significance of the thyrotropin receptor germline polymorphism D727E.
Details
Serval ID
serval:BIB_B5B0784A1CFA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Functional significance of the thyrotropin receptor germline polymorphism D727E.
Journal
Biochemical and Biophysical Research Communications
ISSN
0006-291X (Print)
ISSN-L
0006-291X
Publication state
Published
Issued date
2003
Peer-reviewed
Oui
Volume
301
Number
4
Pages
1051-1056
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
In a toxic thyroid adenoma we identified a novel somatic mutation that constitutively activates the thyrotropin receptor (TSHR). Two heterozygous point mutations at adjacent nucleotides led to a substitution of alanine with asparagine at codon 593 (A593N) in the fifth transmembrane helix of TSHR. This somatic mutation resided on the same TSHR allele with the germline polymorphism D727E. The functional characteristics of the single TSHR mutants A593N and D727E and of the double mutant A593N/D727E were studied in transiently transfected COS-7 cells. The TSHR mutants A593N and A593N/D727E constitutively activated the cAMP cascade, whereas the D727E mutant did not differ from the wild-type TSHR. Surprisingly, the double mutant's specific constitutive activity was 2.3-fold lower than the A593N mutant. Thus, the polymorphism significantly ameliorates G(alphas) protein activation in the presence of the gain-of-function mutation A593N, although it is functionally inert in the context of the wild-type TSHR.
Keywords
Adenoma/genetics, Alleles, Animals, Base Sequence, COS Cells, Cyclic AMP/biosynthesis, DNA, Neoplasm/genetics, Germ-Line Mutation, Heterotrimeric GTP-Binding Proteins/metabolism, Humans, In Vitro Techniques, Polymorphism, Genetic, Receptors, Thyrotropin/genetics, Receptors, Thyrotropin/metabolism, Thyroid Neoplasms/genetics, Thyrotropin/pharmacology, Transfection
Pubmed
Web of science
Create date
20/01/2015 13:51
Last modification date
20/08/2019 15:24