Details Of Published TSH Receptor Mutation
Ala 553 Thr
c.1657G>AInactivating TSH Receptor Mutation
Type
loss
Manifestation
family
Exon
10
Pedigree 1 - Abramowicz et al.
-image missing-
Pedigree 2 - Park et al.
Pedigree 3 - Cangul et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
Wild-Type
Heterozygous
Heterozygous
Compound Heterozygous
Homozygous
Hypothyroid
Hypoplastic Gland + Hypothyroid
P
Index Patient
Molecular Characteristics:
Family 1 - pedigree 1 (Abramowicz et al.):
III/1: Ala553Thr
III/2: Ala553Thr (second cousin to III/1)
IV/2 and IV/4: Ala553Thr/Ala553Thr homozygous
Family 2 - pedigree 2 (Park et al.):
III/1 and III/2: compound heterozygous
A553T/W546X
mother: W546X/wt
father: A553T/wt
Family 3 - pedigree 3(Cangul et al.):
two children homozygous, in a Pakistani family, consanguineous parents (*)
parents and one sibling: heterozygous
Family 4 (Nicoletti et al.):
propositus and mother heterozygous
III/1: Ala553Thr
III/2: Ala553Thr (second cousin to III/1)
IV/2 and IV/4: Ala553Thr/Ala553Thr homozygous
Family 2 - pedigree 2 (Park et al.):
III/1 and III/2: compound heterozygous
A553T/W546X
mother: W546X/wt
father: A553T/wt
Family 3 - pedigree 3(Cangul et al.):
two children homozygous, in a Pakistani family, consanguineous parents (*)
parents and one sibling: heterozygous
Family 4 (Nicoletti et al.):
propositus and mother heterozygous
Clinical Features:
Family 1 - pedigree 1 (Abramowicz et al.):
diagnosis:
IV/2 and IV/4: neonatal congenital hypothyroidism, hypoplastic gland on ultrasound, negative 99mTc scan, high normal Tg levels
Family 2 - pedigree 2 (Park et al.):
diagnosis:
neonatal,
index patients: III/1 and III/2:
severe uncompensated hypothyroidism, prolonged jaundice, macroglossia, hoarse cry, normal development, athyreosis
mother: compensated TSH resistance, mild thyroid hypoplasia, oligomenorrhoea, edema, weight gain, depression, diagnosis at 20yrs
I/1 (grandfather, deceased), II/1: hypothyroidism in adult life, no data available
II/3: euthyroid
Family 3 - pedigree 3 (Cangul et al.):
no I131 uptake, severe thyroid hypoplasia in two children
diagnosis:
IV/2 and IV/4: neonatal congenital hypothyroidism, hypoplastic gland on ultrasound, negative 99mTc scan, high normal Tg levels
Family 2 - pedigree 2 (Park et al.):
diagnosis:
neonatal,
index patients: III/1 and III/2:
severe uncompensated hypothyroidism, prolonged jaundice, macroglossia, hoarse cry, normal development, athyreosis
mother: compensated TSH resistance, mild thyroid hypoplasia, oligomenorrhoea, edema, weight gain, depression, diagnosis at 20yrs
I/1 (grandfather, deceased), II/1: hypothyroidism in adult life, no data available
II/3: euthyroid
Family 3 - pedigree 3 (Cangul et al.):
no I131 uptake, severe thyroid hypoplasia in two children
Treatment:
L-thyroxine
Functional Characteristics:
cAMP
(basal)
(basal)
cAMP
(TSH)
(TSH)
IP
(basal)
(basal)
IP
(TSH)
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
-
+
~
0
-
-
4
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:
Abramowicz et al.
J. Clin. Invest. 99: 3018-3024
Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland
1997
Reference 2:
Cangul et al.
Clin Endocrinol (Oxf) 73:671-677.
Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.
2010
Reference 3:
Nicoletti et al.
J Clin Endocrinol Metab 94:4187-4194.
Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism.
2009
Reference 4:
Park et al.
Clin Endocrinol (Oxf) 60:220-227.
Congenital hypothyroidism and apparent athyreosis with compound heterozygosity or compensated hypothyroidism with probable hemizygosity for inactivating mutations of the TSH receptor.
2004