Details Of Published TSH Receptor Mutation
Ser 281 Asn
c.842G>AConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
sporadic
Exon
9
Pedigree 1 (Grüters et al.)
-image missing-
Pedigree 2 (Chester et al.)
-image missing-
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
P1/V/2 (Grüters et al.):
Note:
Blue marked individuals for additional polymorphism:
Arg 528 His
(III/1, IV/1, IV/2, V/2, V/3)
Note:
Blue marked individuals for additional polymorphism:
Arg 528 His
(III/1, IV/1, IV/2, V/2, V/3)
Clinical Features:
Patient 1 (Grüters et al.):
onset: P1/V/2: neonatal
diagnosis:
P1/V/2: 4 months, premature birth (36 weeks),staring eyes, surgery for craniosynostosis at 13 months
P1/IV/2: 17yr, positive TPO antibodies
P1/III/1: 32 yr, positive TPO antibodies
onset: P1/V/2: neonatal
diagnosis:
P1/V/2: 4 months, premature birth (36 weeks),staring eyes, surgery for craniosynostosis at 13 months
P1/IV/2: 17yr, positive TPO antibodies
P1/III/1: 32 yr, positive TPO antibodies
Treatment:
P1/V/2 (Grüters et al.):
thiamazol, relapse after pause, subtotal TE at 6 yr
P1/VI/2: antithyroid drugs
P1/III/1: TE at 51 yr
thiamazol, relapse after pause, subtotal TE at 6 yr
P1/VI/2: antithyroid drugs
P1/III/1: TE at 51 yr
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2.2-5.3
0.7-1.2
0.6-1.3
0.5-1.3
~
-
1
7.9+/-0.1;15.1+/-2.9
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:
Grüters et al.
J. Clin. Endocrinol. Metab. 83: 1431-1436
Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor
1998
Reference 2:
Duprez et al.
FEBS Lett 409: 469-474
Constitutive activation of the TSH receptor by spontaneous mutations affecting the N-terminal extracellular domain
1997
Reference 3:
Ho SC et al.
Endocrinology 142: 2760-2767
Effects of mutations involving the highly conserved S281HCC motif in the extracellular domain of the thyrotropin (TSH) receptor on TSH binding and constitutive activity.
2001
Reference 4:
Chester et al.
J Pediatr Endocrinol Metab. 21: 479-86
Congenital neonatal hyperthyroidism caused by germline mutations in the TSH receptor gene
2008
Reference 5:
Gozu et al.
Thyroid 18:499-508
A new silent germline mutation of the TSH receptor: coexpression in a hyperthyroid family member with a second activating somatic mutation.
2008
Reference 6:
Jäschke et al.
Endocrinology 147:1753-1760
An aromatic environment in the vicinity of serine 281 is a structural requirement for thyrotropin receptor function.
2006
Reference 7:
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
Reference 8:
Kinjo S et al.
International journal of pediatric endocrinology
A case of 3 months old Japanese boy with sporadic congenital none-autoimmune hyperthyroidism
2015