Details Of Published TSH Receptor Mutation
Ile 568 Thr
c.1703T>CConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
sporadic
Exon
10
Pedigree 1
-image missing-
Pedigree 2 (Watkins et al.)
-image missing-
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
sporadic occurrence in 2 non-related children
P1/III/1: Tonacchera et al.
P2/III/1: Watkins et al.
P1/III/1: Tonacchera et al.
P2/III/1: Watkins et al.
Clinical Features:
Patient 1 (Tonacchera et al.):
onset and diagnosis:
P1/III/1: neonatal, premature birth (35 weeks),
diffuse goiter, advanced bone age,
prominent stare, mild dyslalia
P1/II/1: with low titre TPO
and Tg-Ab, non-toxic goiter
P1/II/2 and P1/I/2: non-toxic goiter
P2/III/1 (Watkins et al.):
onset and diagnosis:
P2/III/1: neonatal, premature birth (35 weeks),
meconium aspiration, pneumothorax, hepatomegaly,
hyperactivity, sleep
difficulties, growth
retardation, advanced bone
age
at 9 months: episodic
supraventricular tachycardia
P2/II/2 hyperthyroid, goiter
P2/II/3: Graves disease
P2/I/1: hypothyroidism
* based on 17 hot nodules investigated by Parma et al. 1995 and 1997, Fuhrer et al. 1997, Trülzsch et al. 2001, Van Sande et al. 1995, Gozu et al. 2006, Georgopoulus et al. 2003, and Nishihara et al. 2009
and 2 activating sporadic germline mutations investigated by Tonacchera et al. 2000 and Watkins et al. 2008
onset and diagnosis:
P1/III/1: neonatal, premature birth (35 weeks),
diffuse goiter, advanced bone age,
prominent stare, mild dyslalia
P1/II/1: with low titre TPO
and Tg-Ab, non-toxic goiter
P1/II/2 and P1/I/2: non-toxic goiter
P2/III/1 (Watkins et al.):
onset and diagnosis:
P2/III/1: neonatal, premature birth (35 weeks),
meconium aspiration, pneumothorax, hepatomegaly,
hyperactivity, sleep
difficulties, growth
retardation, advanced bone
age
at 9 months: episodic
supraventricular tachycardia
P2/II/2 hyperthyroid, goiter
P2/II/3: Graves disease
P2/I/1: hypothyroidism
* based on 17 hot nodules investigated by Parma et al. 1995 and 1997, Fuhrer et al. 1997, Trülzsch et al. 2001, Van Sande et al. 1995, Gozu et al. 2006, Georgopoulus et al. 2003, and Nishihara et al. 2009
and 2 activating sporadic germline mutations investigated by Tonacchera et al. 2000 and Watkins et al. 2008
Treatment:
P1/III/1: Tonacchera et al.:
antithyroid drugs
P2/III/1 Watkins et al.:
antithyroid drugs, L-T4
antithyroid drugs
P2/III/1 Watkins et al.:
antithyroid drugs, L-T4
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
5.2
0.9
0.8-2.2
0.8
-
0.4-0.7
2
1,5,6
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:
Parma et al.
Mol. Endocrinol. 9: 725-733
Somatic mutations causing constitutive activity of the thyrotropin receptor are the major cause of hyperfunctioning thyroid adenomas: identification of additional mutations activating both the cyclic adenosine 3',5'-monophosphate and inositol phosphate-Ca
1995
Reference 2:
Tonacchera et al.
Thyroid 10: 859-863
Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene
2000
Reference 3:
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 4:
Watkins et al.
Endocr Pract.14: 479-83
Persistent neonatal thyrotoxicosis in a neonate secondary to a rare thyroid-stimulating hormone receptor activating mutation: case report and literature review.
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
Reference 6:
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