Details Of Published TSH Receptor Mutation

Trp 546 Stop

c.1637G>A

Inactivating TSH Receptor Mutation

Type
loss
Manifestation
family
Exon
10
Pedigree 1 - De Roux et al.
Pedigree 2 - Jordan et al.
Pedigree 3 - Park et al.
Pedigree 4 - Clifton-Bligh 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 (de Roux et al.):
I/1: Cys390Trp
I/2: Trp546Stop
II/1: Cys390
/Trp546Stop compound heterozygous

Family 2 - pedigree 2 (Jordan et al.):
brothers: homozygous for W546X
parents: heterozygous

two patients from the same population non-related heterozygous




Family 3 - pedigree 3 (Park et al.):
III/1 and III/2: compound heterozygous
W546X/A553T
mother: W546X/wt
father: A553T/wt








Family 4 - pedigree 4 (Clifton-Bligh et al.):
Trp546Stop also with (Arg109)
I/1: Arg109Gln
I/2: Trp546Stop
II/1-2: Arg109Gln/Trp546Stop compound heterozygous 
Clinical Features:
Family 1 - pedigree 1 (de Roux et al.):
II/1 neonatal euthyroid hyperthyrotropinaemia, slightly enlarged thyroid gland on 123 I scan, normal Tg levels




Family 2 - pedigree 2 (Jordan et al.):
two brothers, normal thyroid, no goiter
diagnosed as newborn
brother 1: recurrent infections
brother 2: slight speech impairment, normal hearing, benign bone tumor in left forearm

two non-related patients
patient 1: 58yr male, schizophrenia
patient 2: 56 yr male

Family 3 - pedigree 3 (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 4 - pedigree 4 (Clifton-Bligh et al.):
diagnosis:
II/1: 8 weeks
II/2: neonatal, borderline hypothyroidism, hyperthyroidism under L-thyroxine treatment, normal thyroid gland on ultrasound, normal sciniscan 
Treatment:
L-thyroxine
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
0
0
nd
nd
(0)
nd
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:
Clifton-Bligh et al.
J. Clin. Endocrinol. Metabol. 82: 1094-1100
Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH
1997
Reference 2:
De Roux et al.
J. Clin. Endocrinol. Metabol. 81: 4229-4235
Four families with loss of function mutations of the thyrotropin receptor
1996
Reference 3:
Jordan et al.
J Clin Endocrinol Metab 88:1002-1005.
The W546X mutation of the thyrotropin receptor gene: potential major contributor to thyroid dysfunction in a Caucasian population.
2003
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