Details Of Published TSH Receptor Mutation
Ser 505 Asn
c.1513G>AConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
sporadic
Exon
10
Pedigree 1 (Holzapfel et al.)
-image missing-
Pedigree 2
-image missing-
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
sporadic occurence in two non-related children
"Freiburg" P1/II/3 (Holzapfel et al.)
"Rostock" P2/II/1 (Führer et al.)
Note:
Blue marked individuals are identical. P2/I/1 is married twice.
"Freiburg" P1/II/3 (Holzapfel et al.)
"Rostock" P2/II/1 (Führer et al.)
Note:
Blue marked individuals are identical. P2/I/1 is married twice.
Clinical Features:
"Freiburg" P1/II/3 (Holzapfel et al.):
onset:
P1/II/3: fetal
diagnosis:
P1/II/3: 5 months
excessive thyroid enlargement, staring eyes, speech disturbances, advanced bone age, craniosynostosis
"Rostock" P2/II/1 (Führer et al.):
onset and diagnosis:
P2/II/1: 11 months
excessive thyroid enlargement, advanced bone age
P2/I/2: juvenile goiter
* based on 3 hot nodules investigated by Trülzsch et al. 2001, Gozu et al. 2006 and Nishihara et al. 2009
and on 3 activating sporadic germline mutations investigated by Holzapfel et al. 1997, Holzapfel 1997, and Fuhrer et al. 1999
and on 1 activating familial germline mutation investigated by Vaidya et al. 2004
onset:
P1/II/3: fetal
diagnosis:
P1/II/3: 5 months
excessive thyroid enlargement, staring eyes, speech disturbances, advanced bone age, craniosynostosis
"Rostock" P2/II/1 (Führer et al.):
onset and diagnosis:
P2/II/1: 11 months
excessive thyroid enlargement, advanced bone age
P2/I/2: juvenile goiter
* based on 3 hot nodules investigated by Trülzsch et al. 2001, Gozu et al. 2006 and Nishihara et al. 2009
and on 3 activating sporadic germline mutations investigated by Holzapfel et al. 1997, Holzapfel 1997, and Fuhrer et al. 1999
and on 1 activating familial germline mutation investigated by Vaidya et al. 2004
Treatment:
"Freiburg" P1/II/3 (Holzapfel et al.):
antithyroid drugs ineffective, near-total TE at 27 months, relapse of hyperthyroidism at 6.6yr
"Rostock" P2/II/1 (Führer et al.):
antithyroid drugs, parental incompliance
antithyroid drugs ineffective, near-total TE at 27 months, relapse of hyperthyroidism at 6.6yr
"Rostock" P2/II/1 (Führer et al.):
antithyroid drugs, parental incompliance
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
3
4.5+/-0.3
1,3,4,5
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: 3879-3884
Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene
1997
Reference 2:
Fuhrer et al.
Thyroid 9: 757-761
Variable Phenotype Associated with Ser505Asn-Activating Thyrotropin-receptor Germline Mutation
1999
Reference 3:
Wonerow et al.
Clin. Endocrinol. 53: 461-468
Functional characterization of five constitutively activating thyrotrophin receptor mutations
2000
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