Details Of Published TSH Receptor Mutation
Pro 639 Ser
c.1915C>TConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
family
Exon
10
Pedigree 1 - Khoo et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
Chinese family
Clinical Features:
diagnosis:
I/1: 38yr
II/1: 10yr, goiter
II/2: 5.75yr, goiter
II/3: 5yr, goiter
II/1, II/2, II/3: proptosis
mitral valve prolaps in all affected family members (I/1, II/1-3)
*based on 2 hot nodules investigated by Gözu et al. 2006 and Tonacchera et al. 1998
and on 1 activating familial germline mutation investigated by Khoo et al. 1999
I/1: 38yr
II/1: 10yr, goiter
II/2: 5.75yr, goiter
II/3: 5yr, goiter
II/1, II/2, II/3: proptosis
mitral valve prolaps in all affected family members (I/1, II/1-3)
*based on 2 hot nodules investigated by Gözu et al. 2006 and Tonacchera et al. 1998
and on 1 activating familial germline mutation investigated by Khoo et al. 1999
Treatment:
I/1: antithyroid drugs ineffective, subtotal TE at 41yr,
relapse at 57yr
II/1: antithyroid drugs ineffective, subtotal TE at 21yr
II/2: antithyroid drugs, subtotal TE at 20yr, relapse at 22yr, antithyroid drugs
II/3: antithyroid drugs ineffective, subtotal TE at 21yr
relapse at 57yr
II/1: antithyroid drugs ineffective, subtotal TE at 21yr
II/2: antithyroid drugs, subtotal TE at 20yr, relapse at 22yr, antithyroid drugs
II/3: antithyroid drugs ineffective, subtotal TE at 21yr
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
4.8-5.0
1.1
2.4
0.2
-
0.7
1
2,3
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:
Khoo et al.
J. Clin. Endocrinol. Metab. 84: 1459-1462
A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family
1999
Reference 2:
Tonacchera et al.
J. Clin. Endocrinol. Metab. 83: 492-498
Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma
1998
Reference 3:
Agretti et al.
Eur J Biochem 270:3839-3847
Proper targeting and activity of a nonfunctioning thyroid-stimulating hormone receptor (TSHr) combining an inactivating and activating TSHr mutation in one receptor.
2003