Details Of Published TSH Receptor Mutation
Asn 670 Ser
c.2009A>GConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
family
Exon
10
Pedigree 1 - Tonacchera et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
Pedigree 1: "Reims-2 Family"
NOTE:
constitutive activity only in HEK-cells, not in COS-7 cells
NOTE:
constitutive activity only in HEK-cells, not in COS-7 cells
Clinical Features:
diagnosis:
III/1: 17 yr (index patient)
III/1, III/3, II/4, II/5, I/1:
diffuse goiter
*based on 1 activating familial germline mutation investigated by Tonacchera et al. 1996
III/1: 17 yr (index patient)
III/1, III/3, II/4, II/5, I/1:
diffuse goiter
*based on 1 activating familial germline mutation investigated by Tonacchera et al. 1996
Treatment:
III/1: methimazole ineffective,
radioiodine treatment, euthyroid since
radioiodine treatment, euthyroid since
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
1.7-2.4
0.6
n.d.
n.d.
-
1.0
1
0.5±0.1;2.5
2
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:
Tonacchera et al.
J. Clin. Endocrinol. Metab. 81: 547-554
Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia
1996
Reference 2:
Mueller et al.
Thyroid. 19(7):765-73
Cases of borderline in vitro constitutive thyrotropin receptor activity: how to decide whether a thyrotropin receptor mutation is constitutively active or not?
2009
Reference 3:
Neumann et al.
Mol Endocrinol. 15:1294-305.
A free carboxylate oxygen in the side chain of position 674 in transmembrane domain 7 is necessary for TSH receptor activation.
2001