Document Detail

Substitutions of tyrosine 601 in the human thyrotropin receptor result in increase or loss of basal activation of the cyclic adenosine monophosphate pathway and disrupt coupling to Gq/11.
MedLine Citation:
PMID:  10691307     Owner:  NLM     Status:  MEDLINE    
Constitutively activating mutations of the thyrotropin (TSH) receptor have been identified as a molecular cause of toxic adenomas, nonautoimmune familial hyperthyroidism, and sporadic congenital hyperthyroidism. By analyzing genomic DNA from a toxic adenoma, we detected a novel somatic mutation in codon 601, tyrosine to asparagine (Y601N), a residue located in the carboxyterminal part of the fifth transmembrane helix. This codon is also notable for the presence of a polymorphic variant, Y601H. These two naturally occurring substitutions (Y601N and Y601H) were analyzed together with an artificial mutation, Y601F, to study the role of this residue for receptor function further. Transient transfection assays revealed that the Y601N mutation results in constitutive activation of the cyclic adenosine monophosphate (cAMP) pathway, but that it is unable to couple to Gq/11. Y601H and Y601F do not display basal activity while retaining responsiveness to TSH, but also lose the ability to induce inositol phosphate accumulation in response to TSH. These studies define Y601N as a mutation that selectively activates the cAMP pathway, and they confirm that Y601H is not a silent polymorphism. In conclusion, residue Y601 has an important role for the characteristic constitutive basal activity of the TSH receptor and coupling to Gq/11.
O K Arseven; W P Wilkes; J L Jameson; P Kopp
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Thyroid : official journal of the American Thyroid Association     Volume:  10     ISSN:  1050-7256     ISO Abbreviation:  Thyroid     Publication Date:  2000 Jan 
Date Detail:
Created Date:  2000-03-13     Completed Date:  2000-03-13     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9104317     Medline TA:  Thyroid     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  3-10     Citation Subset:  IM    
Division of Endocrinology, Metabolism & Molecular Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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MeSH Terms
Amino Acid Sequence / genetics
Amino Acid Substitution / genetics
Cyclic AMP / metabolism*
GTP-Binding Proteins / metabolism*
Molecular Sequence Data
Mutation / genetics,  physiology
Receptors, Thyrotropin / genetics*
Thyrotropin / metabolism
Reg. No./Substance:
0/Receptors, Thyrotropin; 60-92-4/Cyclic AMP; 9002-71-5/Thyrotropin; EC 3.6.1.-/GTP-Binding Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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