Details Of Published TSH Receptor Mutation

Met 453 Thr

c.1358T>C

Constitutively Activating TSH Receptor Mutation

Type
gain
Manifestation
somatic
Exon
10
Molecular Characteristics:
default 
Clinical Features:
based on 49 hot nodules investigated by Parma et al. 1997, Duprez et al. 1997, Trülzsch et al. 2001, Gozu et al. 2006, Georgopulos et al. 2003, Vanvooren et al. 2002, Kraemer et al. 2009, Paloz-Paz et al. 2009 and Nishihara et al. 2009, Eszlinger et al. 2014, Agretti et al. 2013, Stephenson et al. 2020
and 2 sporadic activating germline mutations investgated by de Roux et al. 1996 and Lavard et al. 1999
and 1 familial activating germline mutation investigated by Supornsilchai et al. 2009
and 1 hot thyroid carcinoma investigated by Mircescu et al. 2000 
Treatment:
default
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
5.7-7.0
0.8
1.0
0.8-1.0
nd
0.66
49
5.2+/-0.8
1,10,11
Legend:
cAMP (basal): basal in vitro cAMP production of mutant over wild-type TSHR
cAMP (TSH): maximal in vitro cAMP production of mutant over wild-type TSHR
IP (basal): basal in vitro IP production of mutant over wild-type TSHR
IP (TSH): maximal in vitro IP production of mutant over wild-type TSHR
TSH-binding: maximal TSH-binding compared to the wild-type TSHR
Cell surface expression: cell surface expression of mutant compared to WT-TSHR
LRA: linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125I-bTSH binding or FACS analysis compared to the wild-type TSHR
Prevalence: Prevalence of (somatic and germline) activating mutations*
Ref: Reference for functional characterization
Child: Found in children.
Reference 1:
De Roux et al.
J. Clin. Endocrinol. Metab. 81: 2023-2026
A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism.
1996
Reference 2:
Parma et al.
J. Clin. Endocrinol. Metab. 82: 2695-2701
Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas
1997
Reference 3:
Duprez et al.
J. Clin. Endocrinol. Metab. 82: 306-308
Two autonomous nodules of a patient with multinodular goiter harbor different activating mutations of the thyrotropin receptor gene
1997
Reference 4:
Trülzsch et al.
J. Mol. Med. 78: 684-691
Detection of thyroid-stimulating hormone receptor and Gsalpha mutations: in 75 toxic thyroid nodules by denaturing gradient gel electrophoresis.
2001
Reference 5:
Gozu et al.
Eur J Endocrinol. 155: 535-45
Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey.
2006
Reference 6:
Palos-Paz et al.
Eur J Endocrinol. 159: 623-31
Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine-deficient area in NW Spain.
2008
Reference 7:
Georgopoulos et al.
Eur J Endocrinol. 149: 287-92
Autonomously functioning thyroid nodules in a former iodine-deficient area commonly harbor gain-of-function mutations in the thyrotropin signaling pathway.
2003
Reference 8:
Vanvooren et al.
Eur J Endocrinol. 147: 287-91
Oncogenic mutations in the thyrotropin receptor of autonomously functioning thyroid nodules in the Japanese population.
2002
Reference 9:
Kraemer et al.
J Pediatr Endocrinol Metab. 22: 269-74
Activating TSH-receptor mutation (Met453Thr) as a cause of adenomatous non-autoimmune hyperthyroidism in a 3-year-old boy.
2009
Reference 10:
Nishihara et al.
Endocr J. 56:791-8
Prevalence of TSH receptor and Gsalpha mutations in 45 autonomously functioning thyroid nodules in Japan.
2009
Reference 11:
Jäschke et al.
Cell Mol Life Sci 65:4028-4038
Preferences of transmembrane helices for cooperative amplification of G(alpha)s and G (alpha)q signaling of the thyrotropin receptor.
2008
Reference 12:
Lüblinghoff et al.
J Endocrinol Invest 33:228-233
Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism.
2010
Reference 13:
Eszlinger, Markus, et al.
Molecular and cellular endocrinology 
Somatic mutations in 33 benign and malignant hot thyroid nodules in children and adolescents
2014
Reference 14:
Agretti et al.
Clinical endocrinology
Prevalence of activating thyrotropin receptor and gsa gene mutations in paediatric thyroid toxic adenomas: a multicentric italian study
2013
Reference 15:
Stephenson et al.
Thyroid
Sensitive Sequencing Analysis Suggests Thyrotropin Receptor and Guanine Nucleotide-Binding Protein G Subunit Alpha as Sole Driver Mutations in Hot Thyroid Nodules
2020