Details Of Published TSH Receptor Mutation
Ile 486 Met
c.1458C>GConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
somatic
Exon
10
Molecular Characteristics:
default
Clinical Features:
based on 13 hot nodules investigated by Parma et al. 1995 and 1997, Tonacchera et al. 1998 and 2000, Van Sande et al. 1995, Vanvooren et al. 2002, Mon et al. 2018, Sanack et al. 2011, Nishihara et al. 2009 and Stephenson et al. 2020
Treatment:
default
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
3.3-4.3
1.1
1.2-1.7
1.8
-
0.5-0.8
13
5.1 +/- 0.6
1,11
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:
Parma et al.
Mol. Endocrinol. 9: 725-733
Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca
1995
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:
Tonacchera et al.
J. Clin. Endocrinol. Metab. 83: 492-498
Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma
1998
Reference 4:
Van Sande et al.
J. Clin. Endocrinol. Metab. 80: 2577-2585
Somatic and germline mutations of the TSH receptor gene in thyroid diseases
1995
Reference 5:
Tonacchera et al.
Thyroid 8: 559-564
Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter
1998
Reference 6:
Tonacchera et al.
J Clin Endocrinol Metab. 85: 2270-4
Activating thyrotropin receptor mutations are present in nonadenomatous hyperfunctioning nodules of toxic or autonomous multinodular goiter.
2000
Reference 7:
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 8:
Sancak et al.
Horm Metab Res. 43:562-8
High Prevalence of TSHR/Gsalpha Mutation-negative Clonal Hot Thyroid Nodules (HNs) in a Turkish Cohort
2011
Reference 9:
Agretti et al.
Eur J Biochem 270:3839-3847
Proper targeting and activity of a nonfunctioning thyroid-stimulating hormone receptor (TSHr) combining an inactivating and activating TSHr mutation in one receptor.
2003
Reference 10:
Kleinau et al.
Cell Mol Life Sci 65:3664-3676
Molecular and structural effects of inverse agonistic mutations on signaling of the thyrotropin receptor--a basally active GPCR.
2008
Reference 11:
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