Details Of Published TSH Receptor Mutation

Thr 632 Ile

c.1895C>T

Constitutively Activating TSH Receptor Mutation

Type
gain
Manifestation
sporadic
Exon
10
Pedigree 1 (Kopp et al.)
-image missing-
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
default 
Clinical Features:
onset and diagnosis:
II/1: neonatal, premature birth (32 weeks)
multinodular goiter at 3yr, proptosis, mental retardation, craniosynostosis

*based on 50 hot nodules investigated by Paschke et al. 1994, Parma et al. 1997, Duprez et al. 1997, Russo et al. 1996, Holzapfel et al. 1997, Porcellini et al. 1994, Tonacchera et al. 1998, Fuhrer et al. 1997, Tassi et al. 1999, Derwahl et al. 1996, Tonacchera et al. 1998 and 2000, Georgopoulos et al. 2003, Gozu et al. 2005 and 2006, Trulzsch et al. 2001, Palos-Paz et al. 2008, Sancak et al. 2011, Nishihara et al. 2009
and on 3 activating sporadic germline mutation investigated by Kopp et a. 1997, Chawla et al. 2015, and Stephenson 2018
and on 1 hot thyroid carcinoma investigated by Spambalg et al. 1996 
Treatment:
antithyroid drugs and radio-iodine therapy ineffective, near-total TE at 3yr,
relapse of goiter at 14yr,
relapse of thyrotoxicosis at 19yr
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
3.7-5.0
0.8-1.0
1.0-1.3
0.7-1.0
-
n.d.
3
14.5┬▒2.7
2,4,5
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.
Thyroid 7: 765-769
Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene
1997
Reference 2:
Paschke et al.
J. Clin. Endocrinol. Metab. 79: 1785-1789
Identification and functional characterization of two new somatic mutations causing constitutive activation of the thyrotropin receptor in hyperfunctioning autonomous adenomas of the thyroid
1994
Reference 3:
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 4:
Kosugi et al.
FEBS Lett 356: 291-294
Constitutive activation of cyclic AMP but not phosphatidylinositol signaling caused by four mutations in the 6th transmembrane helix of the human thyrotropin receptor.
1994
Reference 5:
L├╝blinghoff et al.
J Endocrinol Invest 33:228-233
Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism.
2010
Reference 6:
Chawla et al.
Thyroid
Squamosal suture craniosynostosis due to hyperthyroidism caused by an activating thyrotropin receptor mutation (T632I)
2015
Reference 7:
Stephenson et al
Canadian Journal of Diabetes
Advanced Bone Age Present in a Neonatal Case of Sporadic Non-Autoimmune Hyperthyroidism Before Onset of Symptoms
2018