Details Of Published TSH Receptor Mutation
Ser 505 Asn
c.1513G>AConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
family
Exon
10
Pedigree 1 - Vaidya et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
default
Clinical Features:
diagnosis:
III/2: 19 months (index patient), diffuse goiter
III/1: 4.3yr
II/1: 9yr, goiter
III/2: TSH binding inhibitory immunoglobulin (TBII) borderline positive
III/1: thyroid microsomal and thyroglobulin antibodies strongly positive, gastro-oesophageal reflux at 4yr
based on 3 hot nodules investigated by Trülzsch et al. 2001, Gozu et al. 2006 and Nishihara et al. 2009
and on 2 activating sporadic germline mutations investigated by Holzapfel et al. 1997 and Fuhrer et al. 1999
and on 1 activating familial germline mutation investigated by Vaidya et al. 2004
III/2: 19 months (index patient), diffuse goiter
III/1: 4.3yr
II/1: 9yr, goiter
III/2: TSH binding inhibitory immunoglobulin (TBII) borderline positive
III/1: thyroid microsomal and thyroglobulin antibodies strongly positive, gastro-oesophageal reflux at 4yr
based on 3 hot nodules investigated by Trülzsch et al. 2001, Gozu et al. 2006 and Nishihara et al. 2009
and on 2 activating sporadic germline mutations investigated by Holzapfel et al. 1997 and Fuhrer et al. 1999
and on 1 activating familial germline mutation investigated by Vaidya et al. 2004
Treatment:
III/2: total TE at 6yr, relapse at 8yr, antithyroid drugs
III/1: total TE at 8yr, euthyroid with L-T4
II/1: antithyroid drugs ineffective, subtotal TE at 13yr, further thyroid resection at 19yr, local irradtion with Telecobalt at 21yr
relapse at 23yr, euthyroid with antithyroid medication
III/1: total TE at 8yr, euthyroid with L-T4
II/1: antithyroid drugs ineffective, subtotal TE at 13yr, further thyroid resection at 19yr, local irradtion with Telecobalt at 21yr
relapse at 23yr, euthyroid with antithyroid medication
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
5-6.5
1.1
0.8-0.9
1-1.2
0.8
1
4.5+/-0.3
1,2,4,5
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:
Holzapfel et al.
J. Clin. Endocrinol. Metab. 82: 4229-4233
Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters
1997
Reference 2:
Wonerow et al.
J. Biol. Chem. 273: 7900-7905
Deletions in the third intracellular loop of the thyrotropin receptor. A new mechanism for constitutive activation.
1998
Reference 3:
Vaidya et al.
Clin Endocrinol. 60: 711-8
Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation.
2004
Reference 4:
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 5:
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