Details Of Published TSH Receptor Mutation
Arg 609 Stop
c.1825C>TInactivating TSH Receptor Mutation
Type
loss
Manifestation
family
Exon
10
Pedigree 1 - Tiosano et al.
Pedigree 2 - Richter-Unruh et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
Wild-Type
Heterozygous
Heterozygous
Compound Heterozygous
Homozygous
Hypothyroid
Hypoplastic Gland + Hypothyroid
P
Index Patient
Molecular Characteristics:
truncated TSHR, biologically inactive
Family 1 - pedigree 1 (Tiosano et al.):
Inbred Beduin kindred (4 nuclear families)
VII/1-2, VII/8, VII/10-12: Arg609Stop/Arg609Stop homozygous novel DdeI restriction site
Note:
Arrow indicates patients with hypoadrenocortisolism
Family 2 - pedigree 2 (Richter-Unruh et al.):
Turkish family, I/1* and I/2*: consanguineous parents
I/1 (father): R609X/wt
I/2 (mother): R609X/wt
II/1, 2, 4 (boys): R609X homozygous
II/3 (girl): R609X homozygous
Family 1 - pedigree 1 (Tiosano et al.):
Inbred Beduin kindred (4 nuclear families)
VII/1-2, VII/8, VII/10-12: Arg609Stop/Arg609Stop homozygous novel DdeI restriction site
Note:
Arrow indicates patients with hypoadrenocortisolism
Family 2 - pedigree 2 (Richter-Unruh et al.):
Turkish family, I/1* and I/2*: consanguineous parents
I/1 (father): R609X/wt
I/2 (mother): R609X/wt
II/1, 2, 4 (boys): R609X homozygous
II/3 (girl): R609X homozygous
Clinical Features:
Family 1 - pedigree 1 (Tiosano et al.):
diagnosis:
neonatal
VII/1-2, VII/8, VII/10-12: congenital hypothyroidism, hypoplastic gland on ultrasound, negative 99mTc scan
VII/5, VII/8-10: congenital hypocortisolism
Family 2 - pedigree 2 (Richter-Unruh et al.):
diagnosis: neonatal, euthyroid hyperthyrotropinaemia, hypoplastic gland on ultrasound, normal development (II/1, II/2, II/4)
psychomotor and mental retardation (II/3)
Family 3 - Cangul et al. no pedigree. Congenital hypothyroidism
diagnosis:
neonatal
VII/1-2, VII/8, VII/10-12: congenital hypothyroidism, hypoplastic gland on ultrasound, negative 99mTc scan
VII/5, VII/8-10: congenital hypocortisolism
Family 2 - pedigree 2 (Richter-Unruh et al.):
diagnosis: neonatal, euthyroid hyperthyrotropinaemia, hypoplastic gland on ultrasound, normal development (II/1, II/2, II/4)
psychomotor and mental retardation (II/3)
Family 3 - Cangul et al. no pedigree. Congenital hypothyroidism
Treatment:
L-thyroxine (+ treatment of hypocortisolism)
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
nd
nd
nd
nd
nd
nd
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:
Tiosano et al.
Thyroid 9: 887-894
The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor
1999
Reference 2:
Richter-Unruh et al.
Thyroid 14:971-974.
Congenital primary hypothyroidism in a turkish family caused by a homozygous nonsense mutation (R609X) in the thyrotropin receptor gene.
2004
Reference 3:
Cangul, Hakan, et al.
Journal of Pediatric Endocrinology and Metabolism
A nonsense thyrotropin receptor gene mutation (R609X) is associated with congenital hypothyroidism and heart defects
2014