Details Of Published TSH Receptor Mutation
Ser 281 Thr
c.842G>CConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
somatic
Exon
9
Molecular Characteristics:
default
Clinical Features:
based on 6 hot nodules investigated by Parma et al. 1997, Duprez et al. 1997, Gozu et al. 2006, Paloz-Paz et al. 2008
Treatment:
default
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2.2-4.4
0.9-1.0
0.7-1.0
0.7-1.0
nd
0.76
6
7.0+/-1.3
3,8,9
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:
Grüters et al.
J. Clin. Endocrinol. Metab. 83: 1431-1436
Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor
1998
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.
FEBS Lett 409: 469-474
Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain
1997
Reference 4:
Ho SC et al.
Endocrinology 142: 2760-2767
Effects of mutations involving the highly conserved S281HCC motif in the extracellular domain of the thyrotropin (TSH) receptor on TSH binding and constitutive activity.
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:
Gozu et al.
Thyroid 18:499-508
A new silent germline mutation of the TSH receptor: coexpression in a hyperthyroid family member with a second activating somatic mutation.
2008
Reference 8:
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 9:
Neumann et al.
Eur J Endocrinol 152:625-634
Interactions between the extracellular domain and the extracellular loops as well as the 6th transmembrane domain are necessary for TSH receptor activation.
2005