Details Of Published TSH Receptor Mutation
Leu 512 Gln
c.1535T>AConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
sporadic
Exon
10
Pedigree 1
-image missing-
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
default
Clinical Features:
onset and diagnosis:
1: II/1: neonatal, premature birth (32 weeks)
excessive thyroid enlargement (370ml at 20yr), mental retardation, advanced bone age, craniosynostosis with neurosurgery at 1.5yr, dilation of cerebral ventricles (CT), perodactylia
2: II/1 20y goiter, overt hyperthyroidism
based on 7 hot nodules investigated by Trülzsch et al. 2001, Gozu et al. 2006, Paloz-Paz et al. 2008, Georgopulos et al. 2003 and Sykiotis et al. 2002
and on 1 activating sporadic germline mutation investigated by Nishihara et al. 2006 and Nishihara et al. 2014
1: II/1: neonatal, premature birth (32 weeks)
excessive thyroid enlargement (370ml at 20yr), mental retardation, advanced bone age, craniosynostosis with neurosurgery at 1.5yr, dilation of cerebral ventricles (CT), perodactylia
2: II/1 20y goiter, overt hyperthyroidism
based on 7 hot nodules investigated by Trülzsch et al. 2001, Gozu et al. 2006, Paloz-Paz et al. 2008, Georgopulos et al. 2003 and Sykiotis et al. 2002
and on 1 activating sporadic germline mutation investigated by Nishihara et al. 2006 and Nishihara et al. 2014
Treatment:
1: antithyroid drugs ineffective, poor compliance, radio-iodine therapy (13mCi) at 20yr, subclinical hyperthyroidism with L-T4 and thiamazole
2: antithyroid drugs, radioactive iodine therapy
2: antithyroid drugs, radioactive iodine therapy
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
3.7-4.6
0.7-0.9
0.9
0.5
ND
0.9-1.0
1
4.5+/-0.7
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:
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 2:
Nishihara et al.
Endocr J. 53: 735-40
Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient.
2006
Reference 3:
Jäschke et al.
Cell Mol Life Sci 65:4028-4038
Preferences of transmembrane helices for cooperative amplification of G(alpha)s and G (alpha)q signaling of the thyrotropin receptor.
2008
Reference 4:
Lüblinghoff 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 5:
Nishihara, Eijun, et al.
Thyroid
Prevalence of thyrotropin receptor germline mutations and clinical courses in 89 hyperthyroid patients with diffuse goiter and negative anti-thyrotropin receptor antibodies.
2014