000130783 001__ 130783
000130783 005__ 20240201145619.0
000130783 0247_ $$2doi$$a10.1111/cen.14215
000130783 0248_ $$2sideral$$a118734
000130783 037__ $$aART-2020-118734
000130783 041__ $$aeng
000130783 100__ $$aCaron, P.
000130783 245__ $$aNew variant (Val597Ile) in transmembrane region of the TSH receptor with human chorionic gonadotropin hypersensitivity in familial gestational hyperthyroidism
000130783 260__ $$c2020
000130783 5060_ $$aAccess copy available to the general public$$fUnrestricted
000130783 5203_ $$aObjectives Only two mutations at the lysine 183 amino acid in the extracellular N-terminal domain of human TSH receptor (hTSHR) have been associated with hypersensitivity to hCG and familial gestational hyperthyroidism. Design Describe a new variant of the TSHR gene with hCG hypersensitivity found in two women of the same family diagnosed with gestational hyperthyroidism. Patients A 38-year-old woman was seen during the first trimester of her second pregnancy for thyrotoxicosis with increased fT3 and fT4 concentrations and low TSH levels without anti-TSH receptor antibody. Thyrotoxicosis improved spontaneously during the 2nd trimester and persisted at the 3rd trimester. Similar clinical symptoms (weight loss, nausea, vomiting) were also reported during the first trimester of her first pregnancy and the first pregnancy of her mother. Results DNA sequencing of the hTSHR gene of this woman and her mother identifies a heterozygous variant changing valine to isoleucine residue at codon 597 in the transmembrane domain (TMD) of this receptor. In vitro functional studies of this variant showed increased constitutive activity in regard to the basal level of cAMP and IP3 production and to the low cell-surface expression, while response to TSH was reduced compared to that of the wild-type receptor. The Val597Ile variant presented a dose-dependent increase in cAMP response to hGC and human luteinizing hormone (hLH). Simulation of the protein dynamics showed a high structural impact of the Val597Ile variant on helices 3 (TMH3) and 5 (TMH5) of the transmembrane domain participating to constitutive activity and hCG sensitivity. Conclusion We describe a new variant in the transmembrane region of the hTSHR gene with increased constitutive activity and hCG hypersensitivity in familial gestational hyperthyroidism.
000130783 536__ $$9info:eu-repo/grantAgreement/ES/MINECO/BFU2016-78232-P
000130783 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000130783 590__ $$a3.478$$b2020
000130783 591__ $$aENDOCRINOLOGY & METABOLISM$$b89 / 144 = 0.618$$c2020$$dQ3$$eT2
000130783 592__ $$a1.054$$b2020
000130783 593__ $$aEndocrinology, Diabetes and Metabolism$$c2020$$dQ2
000130783 593__ $$aEndocrinology$$c2020$$dQ2
000130783 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/acceptedVersion
000130783 700__ $$aBroussaud, S.
000130783 700__ $$0(orcid)0000-0002-1896-7805$$aGalano-Frutos, Juan José$$uUniversidad de Zaragoza
000130783 700__ $$0(orcid)0000-0002-2879-9200$$aSancho, Javier$$uUniversidad de Zaragoza
000130783 700__ $$aSavagner, F.
000130783 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000130783 773__ $$g93, 3 (2020), 339-345$$pClin. endocrinol.$$tCLINICAL ENDOCRINOLOGY$$x0300-0664
000130783 8564_ $$s9615873$$uhttps://zaguan.unizar.es/record/130783/files/texto_completo.pdf$$yPostprint
000130783 8564_ $$s1517813$$uhttps://zaguan.unizar.es/record/130783/files/texto_completo.jpg?subformat=icon$$xicon$$yPostprint
000130783 909CO $$ooai:zaguan.unizar.es:130783$$particulos$$pdriver
000130783 951__ $$a2024-02-01-14:52:34
000130783 980__ $$aARTICLE