Details Of Published TSH Receptor Mutation
Ile 486 Phe
c.1457T>AConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
carcinoma
Exon
10
Molecular Characteristics:
default
Clinical Features:
follicular carcinoma with clinical phenotype of "hot nodule"
* based on 13 hot nodules investigated by Parma et al. 1995 and 1997, Trülzsch et al. 2001, Van Sande et al. 1995, Tonacchera et al. 2000, Gozu et al. 2006, Paloz-Paz et al. 2008 and Georgopulos et al. 2003
and 2 hot thyroid carcinomas investigated by Camacho et al. 2000 and Bircan et al. 2005
* based on 13 hot nodules investigated by Parma et al. 1995 and 1997, Trülzsch et al. 2001, Van Sande et al. 1995, Tonacchera et al. 2000, Gozu et al. 2006, Paloz-Paz et al. 2008 and Georgopulos et al. 2003
and 2 hot thyroid carcinomas investigated by Camacho et al. 2000 and Bircan et al. 2005
Treatment:
default
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
4.0-8.2
0.8
1.0-3.3
0.4
-
0.2-0.4
2
57.8+/-6.9
1,2,5,6
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:
Claeysen et al.
FEBS Lett 517: 195-200
A conserved Asn in TM7 of the thyrotropin receptor is a common requirement for activation by both mutations and its natural agonist.
2002
Reference 3:
Camacho et al.
Thyroid 10: 1009-1012
A Phe 486 thyrotropin receptor mutation in an autonomously functioning follicular carcinoma that was causing hyperthyroidism.
2000
Reference 4:
Bircan et al.
Abstract Book 32nd Annual Meeting of the European Thyroid Association, 01.-05.09.2007 Leipzig.
The Second Follicular Thyroid Carcinoma Presenting as a Hot Nodule with a Somatic I486F TSH-Receptor (TSHR) Gene Mutation
2005
Reference 5:
Ho et al.
Mol Cell Endocrinol 245:158-168
Cysteine 390 mutation of the TSH receptor modulates its ectodomain as an inverse agonist on the serpentine domain with decrease in basal constitutive activity.
2005
Reference 6:
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