Details Of Published TSH Receptor Mutation
Ser 505 Arg
c.1513G>AConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
family
Exon
10
Pedigree 1 - Pohlenz et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
hereditary occurrence in 2 non-related families
Family 1: "Lausanne family" - Pedigree 1: Horton et al.
Family 2 - Pedigree 2: Pohlenz et al.
Family 1: "Lausanne family" - Pedigree 1: Horton et al.
Family 2 - Pedigree 2: Pohlenz et al.
Clinical Features:
Family 1: "Lausanne family" - Pedigree 1 (Horton et al.):
manifestation:
childhood - adolescence
family of Sicilian origin
4 females and 1 male in 3 generations affected
diffuse goiter in all patients
Family 2 - Pedigree 2 (Pohlenz et al.):
diagnosis:
P2/II/1: 6 months (index patient)
P2/I/1: 9yr
* based on 2 activating familial germline mutations investigated by Horton et al. 1987 and Pohlenz et al. 2006
manifestation:
childhood - adolescence
family of Sicilian origin
4 females and 1 male in 3 generations affected
diffuse goiter in all patients
Family 2 - Pedigree 2 (Pohlenz et al.):
diagnosis:
P2/II/1: 6 months (index patient)
P2/I/1: 9yr
* based on 2 activating familial germline mutations investigated by Horton et al. 1987 and Pohlenz et al. 2006
Treatment:
Family 1: "Lausanne family" - Pedigree 1 (Horton et al.):
all patients:
antithyroid medication: relapse after pause
subtotal thyroidectomy: relapse
radioiodine treatment: hypothyroidism in 1 patient and persistent hyperthyroidism in 1 patient
Family 2 - Pedigree 2 (Pohlenz et al.):
P2/II/1: euthyroid without treatment
P2/I/1: subtotal TE at 9yr, euthyroid with antithyroid drugs
all patients:
antithyroid medication: relapse after pause
subtotal thyroidectomy: relapse
radioiodine treatment: hypothyroidism in 1 patient and persistent hyperthyroidism in 1 patient
Family 2 - Pedigree 2 (Pohlenz et al.):
P2/II/1: euthyroid without treatment
P2/I/1: subtotal TE at 9yr, euthyroid with antithyroid drugs
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2.2-2.9
0.7-1.0
1.0
0.5
-
0.6-0.8
2
6.1+/-0.9
2,3,5,7
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:
Horton et al.
Ann Endocrinol (Paris) 48: 92
Hereditary hyperthyroidism with diffuse non autoimmune hyperactivity due to autonomy of function and growth
1987
Reference 2:
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 3:
Kosugi et al.
Eur. J. Endocrinol. 143: 471-477
A novel activating mutation in the thyrotropin receptor gene in an autonomously functioning thyroid nodule developed by a Japanese patient
2000
Reference 4:
Van Sande et al.
J. Clin. Endocrinol. Metab. 80: 2577-2585
Somatic and germline mutations of the TSH receptor gene in thyroid diseases
1995
Reference 5:
Claeysen et al.
FEBS Lett 517: 195-200
A conserved Asn in TM7 of the thyrotropin receptor is a common requirement for activation by both mutations and its natural agonist.
2002
Reference 6:
Pohlenz et al.
Acta Paediatr. 95: 1685-7
Subclinical hyperthyroidism due to a thyrotropin receptor (TSHR) gene mutation (S505R).
2006
Reference 7:
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