Details Of Published TSH Receptor Mutation

Ser 281 Asn

c.842G>A

Constitutively Activating TSH Receptor Mutation

Type
gain
Manifestation
somatic
Exon
9
Molecular Characteristics:
default 
Clinical Features:
based on 12 hot nodules investigated by Parma et al. 1997, Fuhrer et al. 1997, Duprez et al. 1997, Trülzsch et al. 2001, Stephenson et al. 2020, Tonacchera et al. 2000, Gozu et al. 2006, Paloz-Paz et al. 2008, Sancak et al. 2011, Eszlinger et al. 2014, and
and 3 activating germline mutations published by Grüters et al. 1998, Kinjo et al. 2015 and Chester et al. 2008  
Treatment:
default
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2.2-5.3
0.7-1.2
0.6-1.3
0.5-1.3
nd
0.2-0.6
12
7.9+/-0.1;15.1+/-2.9
3,5,10,11,12
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.
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 2:
Fuhrer et al.
J. Clin. Endocrinol. Metab. 82: 3885-3891
Somatic mutations in the thyrotropin receptor gene and not in the Gs alpha protein gene in 31 toxic thyroid nodules
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:
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:
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 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:
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 8:
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 9:
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 10:
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 11:
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 12:
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
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:
Kinjo S et al.
International journal of pediatric endocrinology
A case of 3 months old Japanese boy with sporadic congenital none-autoimmune hyperthyroidism
2015