Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation

<p>Abstract</p> <p>Background</p> <p>Constitutively activating germline mutations in the thyrotropin receptor (TSHR) gene result in non-autoimmune hyperthyroidism and can be transmitted as a dominant trait or occur sporadically. These mutations are mostly located in the...

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Main Authors: Biebermann Heike, Winkler Franziska, Handke Daniela, Grüters Annette, Krude Heiko, Kleinau Gunnar
Format: Article
Language:English
Published: BMC 2011-08-01
Series:Thyroid Research
Online Access:http://www.thyroidresearchjournal.com/content/4/S1/S8
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spelling doaj-9aa1c44d8327497c899076765356f7db2020-11-24T22:06:38ZengBMCThyroid Research1756-66142011-08-014Suppl 1S810.1186/1756-6614-4-S1-S8Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutationBiebermann HeikeWinkler FranziskaHandke DanielaGrüters AnnetteKrude HeikoKleinau Gunnar<p>Abstract</p> <p>Background</p> <p>Constitutively activating germline mutations in the thyrotropin receptor (TSHR) gene result in non-autoimmune hyperthyroidism and can be transmitted as a dominant trait or occur sporadically. These mutations are mostly located in the serpentine part of this G-protein coupled receptor.</p> <p>Methods</p> <p>Sequencing exon 9 and 10 of the thyrotropin receptor gene in a two months old patient identified a mutation which was functionally characterized after transient transfection into COS-7 cells. Cell surface localization was investigated by an ELISA approach and for signalling properties we measured cAMP by alpha screen technology for Gs/adenylyl cyclase activation and use a reporter gene assay for determination of Gq/11 phospholipase C-β activation.</p> <p>Results</p> <p>We detected a heterozygous mutation in the first extracellular loop of the TSHR gene leading to an exchange of an isoleucine residue for asparagine at amino acid position 486 (I486N). Cell surface localization was reduced to 51% of wild-type TSHR. Functional characterization of the mutant receptor revealed constitutive activation of the Gs/adenylyl cyclase pathway, in contrast basal activity of the Gq/11 pathway was comparable to the wild-type. The bovine TSH-induced cAMP accumulation was slightly reduced, but IP3 signaling was impaired.</p> <p>Conclusion</p> <p>We identified a new TSHR germline mutation (I486N) in a neonate with non-autoimmune sporadic hyperthyroidism. The mutation is located at the extracellular loop 1 and exhibits an increase in basal cAMP accumulation, but unexpectedly impairs the capability for TSH induced Gq mediated signaling. The TSHR homology model suggests isoleucine 486 as a potential key-player for induction of signal transduction by an interplay with further activation sensitive extracellular parts.</p> http://www.thyroidresearchjournal.com/content/4/S1/S8
collection DOAJ
language English
format Article
sources DOAJ
author Biebermann Heike
Winkler Franziska
Handke Daniela
Grüters Annette
Krude Heiko
Kleinau Gunnar
spellingShingle Biebermann Heike
Winkler Franziska
Handke Daniela
Grüters Annette
Krude Heiko
Kleinau Gunnar
Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
Thyroid Research
author_facet Biebermann Heike
Winkler Franziska
Handke Daniela
Grüters Annette
Krude Heiko
Kleinau Gunnar
author_sort Biebermann Heike
title Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
title_short Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
title_full Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
title_fullStr Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
title_full_unstemmed Molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
title_sort molecular description of non-autoimmune hyperthyroidism at a neonate caused by a new thyrotropin receptor germline mutation
publisher BMC
series Thyroid Research
issn 1756-6614
publishDate 2011-08-01
description <p>Abstract</p> <p>Background</p> <p>Constitutively activating germline mutations in the thyrotropin receptor (TSHR) gene result in non-autoimmune hyperthyroidism and can be transmitted as a dominant trait or occur sporadically. These mutations are mostly located in the serpentine part of this G-protein coupled receptor.</p> <p>Methods</p> <p>Sequencing exon 9 and 10 of the thyrotropin receptor gene in a two months old patient identified a mutation which was functionally characterized after transient transfection into COS-7 cells. Cell surface localization was investigated by an ELISA approach and for signalling properties we measured cAMP by alpha screen technology for Gs/adenylyl cyclase activation and use a reporter gene assay for determination of Gq/11 phospholipase C-β activation.</p> <p>Results</p> <p>We detected a heterozygous mutation in the first extracellular loop of the TSHR gene leading to an exchange of an isoleucine residue for asparagine at amino acid position 486 (I486N). Cell surface localization was reduced to 51% of wild-type TSHR. Functional characterization of the mutant receptor revealed constitutive activation of the Gs/adenylyl cyclase pathway, in contrast basal activity of the Gq/11 pathway was comparable to the wild-type. The bovine TSH-induced cAMP accumulation was slightly reduced, but IP3 signaling was impaired.</p> <p>Conclusion</p> <p>We identified a new TSHR germline mutation (I486N) in a neonate with non-autoimmune sporadic hyperthyroidism. The mutation is located at the extracellular loop 1 and exhibits an increase in basal cAMP accumulation, but unexpectedly impairs the capability for TSH induced Gq mediated signaling. The TSHR homology model suggests isoleucine 486 as a potential key-player for induction of signal transduction by an interplay with further activation sensitive extracellular parts.</p>
url http://www.thyroidresearchjournal.com/content/4/S1/S8
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