Details Of Published TSH Receptor Mutation
Arg 450 His
c.1349G>AInactivating TSH Receptor Mutation
Type
loss
Manifestation
family
Exon
10
Fu et al.
Pedigree 1 - Nagashima et al.
Pedigree 2 - Ma et al.
Pedigree 3 - Narumi et al.
Pedigree 4 - Tsunekawa
Park 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 (Nagashima et al.):
I/1: Arg450His
I/2: Gly498Ser
II/1: Arg450His
II/2-3: Arg450His/Gly498Ser compound heterozygous Arg450His abolishes 1 AciI restriction site
Family 2 - pedigree 2 (Ma et al.):
propositus: homozygous: R450H
and PM D727E
6 relatives (mother II/1, father II/2, mat. grandma I/2, paternal grandmother I/4, paternal aunt: II/5 and II/6 ): compound heterozygous for R450H and D727E
(Narumi et al. 2009):
Patient 1: Arg450His
Patient 2: G132R/R450H, mother R450H/wt
Patient 3: D403N/R450H
Patient 4: R450H/wt, 2 brothers and mother: R450/wt, father: wt
Patient 5: R450H/wt
Patient 6: A204V/wt, 1 sister: wt, 1 sister and parents: not examined
Tsunekawa et al.:
Family A R450H/V473I/a (1 boy)
Family B R450H/R519C (brother, 2 twin sisters (*))
Family C R450H/R519G (2 brothers)
Kanda et al:
3 homozygous subjects
3 heterozygous patients
Patient 1 and 2 same parents
Patient 4 and 5 same parents
Lee et al.:
mutation in 13 of 18 disease alleles
Narumi et al. 2011:
R450H/T145I
R450H/I661fs
Vigone et al. P162S/R450H
I/1: Arg450His
I/2: Gly498Ser
II/1: Arg450His
II/2-3: Arg450His/Gly498Ser compound heterozygous Arg450His abolishes 1 AciI restriction site
Family 2 - pedigree 2 (Ma et al.):
propositus: homozygous: R450H
and PM D727E
6 relatives (mother II/1, father II/2, mat. grandma I/2, paternal grandmother I/4, paternal aunt: II/5 and II/6 ): compound heterozygous for R450H and D727E
(Narumi et al. 2009):
Patient 1: Arg450His
Patient 2: G132R/R450H, mother R450H/wt
Patient 3: D403N/R450H
Patient 4: R450H/wt, 2 brothers and mother: R450/wt, father: wt
Patient 5: R450H/wt
Patient 6: A204V/wt, 1 sister: wt, 1 sister and parents: not examined
Tsunekawa et al.:
Family A R450H/V473I/a (1 boy)
Family B R450H/R519C (brother, 2 twin sisters (*))
Family C R450H/R519G (2 brothers)
Kanda et al:
3 homozygous subjects
3 heterozygous patients
Patient 1 and 2 same parents
Patient 4 and 5 same parents
Lee et al.:
mutation in 13 of 18 disease alleles
Narumi et al. 2011:
R450H/T145I
R450H/I661fs
Vigone et al. P162S/R450H
Clinical Features:
Family 1 - pedigree 1 (Nagashima et al.):
diagnosis:
neonatal, euthyroid hyperthyrotropinaemia, slightly hypoplastic glands on ultrasound, normal 123-I scan, normal Tg level
Family 2 - pedigree 2 (Ma et al.):
III/1:12yr old girl
Neck ultrasound and 99Tcm neck scan revealed thyroid hypoplasia at day 3
subclinical hypothyroidism
(Narumi et al. 2009):
diagnosis:
P1: 5, boy, normal thyroid, parents not examined
P2: 6, girl, mild hypoplasia
P3: 5,boy, parents, 2 brothes, 1 sister not examined
P4: 4, boy, normal thyroid, 2 brothers, parents not examined
P5: 5, boy
P6: 6, girl normal thyroid
Tsunekawa et al.:
B diagnosed as neonate, ossification centers of knee
Kanda et al:
mild hypothyroidism
Diagnosed on neonatal screening, highly elevated TSH levels
Heterozygous patients: fully or partially compensated hypothyroidism
Patient 4: neonatal screening
Patient 5: mild thyroid hypoplasia
Patient 1-4, 6: normal thyroid volume
Vigone et al. P162S/R450H found in 3 related children (twins and another child from same parents) no parent data
diagnosis:
neonatal, euthyroid hyperthyrotropinaemia, slightly hypoplastic glands on ultrasound, normal 123-I scan, normal Tg level
Family 2 - pedigree 2 (Ma et al.):
III/1:12yr old girl
Neck ultrasound and 99Tcm neck scan revealed thyroid hypoplasia at day 3
subclinical hypothyroidism
(Narumi et al. 2009):
diagnosis:
P1: 5, boy, normal thyroid, parents not examined
P2: 6, girl, mild hypoplasia
P3: 5,boy, parents, 2 brothes, 1 sister not examined
P4: 4, boy, normal thyroid, 2 brothers, parents not examined
P5: 5, boy
P6: 6, girl normal thyroid
Tsunekawa et al.:
B diagnosed as neonate, ossification centers of knee
Kanda et al:
mild hypothyroidism
Diagnosed on neonatal screening, highly elevated TSH levels
Heterozygous patients: fully or partially compensated hypothyroidism
Patient 4: neonatal screening
Patient 5: mild thyroid hypoplasia
Patient 1-4, 6: normal thyroid volume
Vigone et al. P162S/R450H found in 3 related children (twins and another child from same parents) no parent data
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
-
+
nd
nd
+
-
16
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:
Nagashima et al.
Thyroid 11: 551-559
Novel inactivating missense mutations in the thyrotropin receptor gene in Japanese children with resistance to thyrotropin
2001
Reference 2:
Calebiro et al.
J Clin Endocrinol Metab 97:156-160.
Frequent TSH Receptor Genetic Alterations with Variable Signaling Impairment in a Large Series of Children with Nonautoimmune Isolated Hyperthyrotropinemia.
2012
Reference 3:
Kanda et al.
Endocrine 30:383-388.
Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese.
2006
Reference 4:
Lee et al.
Clin Endocrinol (Oxf) 75:715-721.
Molecular screening of the TSH receptor (TSHR) and thyroid peroxidase (TPO) genes in Korean patients with nonsyndromic congenital hypothyroidism.
2011
Reference 5:
Ma et al.
J Pediatr Endocrinol Metab 23:1339-1344.
The R450H mutation and D727E polymorphism of the thyrotropin receptor gene in a Chinese child with congenital hypothyroidism.
2010
Reference 6:
Narumi et al.
J Clin Endocrinol Metab 94:1317-1323.
TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study.
2009
Reference 7:
Tsunekawa et al.
Thyroid 16:471-479.
Identification and functional analysis of novel inactivating thyrotropin receptor mutations in patients with thyrotropin resistance.
2006
Reference 8:
Fu, Chunyun et al.
Clinica Chimica Acta
Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients
2016
Reference 9:
Park et al.
Scientific Reports
Concurrent TSHR mutations and DIO2 T92A polymorphism result in abnormal thyroid hormone metabolism
2018
Reference 10:
Tsunekawa et al.
The Japanese journal of clinical pathology
Thyroid disease caused by receptor abnormality.
2014