Details Of Published TSH Receptor Mutation
Leu 629 Phe
c.1887G>TConstitutively Activating TSH Receptor Mutation
Type
gain
Manifestation
family
Exon
10
Pedigree 1 - Führer et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
Pedigree 1: "Leipzig family"
Clinical Features:
manifestation:
II/4: early childhood
III/1: neonatal (index patient)
III/1: proptosis
* based on 17 hot nodules investigated by Tonacchera et al. 1998 and 2000, Gozu et al. 2005 and 2006, Sancak et al. 2011, Parma et al. 1997, Georgopoulos et al. 2003, Palos-Paz et al. 2008
and on 1 activating familial germline mutation investigated by Fuhrer et al. 1997
II/4: early childhood
III/1: neonatal (index patient)
III/1: proptosis
* based on 17 hot nodules investigated by Tonacchera et al. 1998 and 2000, Gozu et al. 2005 and 2006, Sancak et al. 2011, Parma et al. 1997, Georgopoulos et al. 2003, Palos-Paz et al. 2008
and on 1 activating familial germline mutation investigated by Fuhrer et al. 1997
Treatment:
II/4: methimazole at 12yr,
relapse after pause at 17yr,
subtotal TE at 18yr, 2. relapse at 21yr,
3. relapse at 25yr,
radioiodine at 25yr, L-thyroxine
III/1: methimazole +L-thyroxine, near-total TE at 11yr
relapse after pause at 17yr,
subtotal TE at 18yr, 2. relapse at 21yr,
3. relapse at 25yr,
radioiodine at 25yr, L-thyroxine
III/1: methimazole +L-thyroxine, near-total TE at 11yr
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2.1-6.5
0.8-0.9
1.0-1.1
0.2
~
0.7
1
6.9±0.6
2,3,4,5
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:
Fuhrer et al.
J. Clin. Endocrinol. Metab. 82: 4234-4238
Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism
1997
Reference 2:
Parma et al.
J. Clin. Endocrinol. Metab. 82: 2695-2701
Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas
1997
Reference 3:
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 4:
Wonerow et al.
Clin. Endocrinol. 53: 461-468
Functional characterization of five constitutively activating thyrotrophin receptor mutations
2000
Reference 5:
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