Details Of Published TSH Receptor Mutation
Thr 655 Stop
del655Inactivating TSH Receptor Mutation
Type
loss
Manifestation
family
Exon
10
Pedigree 1 - Gagné et al.
Pedigree 2 - Alberti et al.
Pedigree 3 - Calebiro et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
Wild-Type
Heterozygous
Heterozygous
Compound Heterozygous
Homozygous
Hypothyroid
Hypoplastic Gland + Hypothyroid
P
Index Patient
Molecular Characteristics:
Thr655Stop
A) p.T655CfsX566 (Family 1-3)
Deletion of 2 bases codon 655 in exon 10 resulting in truncation (termination of translation at codon 655), Del AC655
Altered splicing, skipping of exon 6
B) p.Q33PfsX46 (Family 4)
frameshift mutation, (termination of translation at codon 655)
father and son: heterozygous
A) p.T655CfsX566 (Family 1-3)
Deletion of 2 bases codon 655 in exon 10 resulting in truncation (termination of translation at codon 655), Del AC655
Altered splicing, skipping of exon 6
B) p.Q33PfsX46 (Family 4)
frameshift mutation, (termination of translation at codon 655)
father and son: heterozygous
Clinical Features:
Family 1 - pedigree 1 (Gagné et al.):
III/2: G->C+3IVS6
IV/1: Thr655X/G>C+3IVS6 compound heterozygous
diagnosis:
IV/1: neonatal, congenital hypothyroidism, persistent jaundice, myxedematous facies, umbilical hernia, large posterior fontanelle, very hypoplastic gland on ultrasound, negative Tc scan, normal Tg, normal growth and development
II/1: congenital hypothyroidism (clinical athyreosis) no TSHR mutation
Family 2 - pedigree 2 (Alberti et al.):
II/2: Thr655X heterozygous
diagnosis:
II/2: 25yr, euthyroid hyperthyrotropinaemia, slightly hypoplastic gland on ultrasound, normal 99mTc scan
Family 3 - pedigree 3 (Calebiro et al.):
mother, daughter, son: heterozygous for Thr655X
Family 4 - pedigree 4 (Calebiro et al.)
III/2: G->C+3IVS6
IV/1: Thr655X/G>C+3IVS6 compound heterozygous
diagnosis:
IV/1: neonatal, congenital hypothyroidism, persistent jaundice, myxedematous facies, umbilical hernia, large posterior fontanelle, very hypoplastic gland on ultrasound, negative Tc scan, normal Tg, normal growth and development
II/1: congenital hypothyroidism (clinical athyreosis) no TSHR mutation
Family 2 - pedigree 2 (Alberti et al.):
II/2: Thr655X heterozygous
diagnosis:
II/2: 25yr, euthyroid hyperthyrotropinaemia, slightly hypoplastic gland on ultrasound, normal 99mTc scan
Family 3 - pedigree 3 (Calebiro et al.):
mother, daughter, son: heterozygous for Thr655X
Family 4 - pedigree 4 (Calebiro et al.)
Treatment:
L-T4
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
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:
Gagné et al.
J. Clin. Endocrinol. Metabol. 83: 1771-1775
Apparent congenital athyreosis contrasting with normal plasma thyroglobulin levels and associated with inactivating mutations in the thyrotropin receptor gene: are athyreosis and ectopic thyroid DISTINCT entities?
1998
Reference 2:
Alberti et al.
J. Clin. Endocrinol. Metab. 87: 2549-2555
Germline Mutations of TSH Receptor Gene as Cause of Nonautoimmune Subclinical Hypothyroidism
2002
Reference 3:
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