Details Of Published TSH Receptor Mutation

Ser 281 Ile

c.842G>T

Constitutively Activating TSH Receptor Mutation

Type
gain
Manifestation
somatic
Exon
9
Molecular Characteristics:
default 
Clinical Features:
based on 6 hot nodules investigated by Kopp et al. 1997, Schwab et al. 2009 Stephenson et al. 2020,and Nanba et al. 2012 
Treatment:
Nanba et al.: Right hemi-thyroidectomy, methimazole

Schwab et al.: thyroidectomy
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
7-8
0.61
1-3.7
0.6-0.9
0,23
6
25.1+/-7.9
1-3
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:
Kopp et al.
J. Clin. Invest. 100: 1634-1639
Congenital hyperthyroidism caused by a solitary toxic adenoma harboring a novel somatic mutation (serine281 -> isoleucine) in the extracellular domain of the thyrotropin receptor
1997
Reference 2:
Jäschke et al.
Endocrinology 147:1753-1760
An aromatic environment in the vicinity of serine 281 is a structural requirement for thyrotropin receptor function.
2006
Reference 3:
Kleinau et al.
J Biol Chem 282:518-525
Contacts between extracellular loop two and transmembrane helix six determine basal activity of the thyroid-stimulating hormone receptor.
2007
Reference 4:
Schwab, Karl Otfried, et al.
The Journal of Pediatrics
Autonomous thyroid adenoma: only an adulthood disease?
2009
Reference 5:
Nanba, Kazutaka, et al.
Endocrine journal
Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas
2012
Reference 6:
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