Details Of Published TSH Receptor Mutation

Glu 34 Lys

c.100G>A

Inactivating TSH Receptor Mutation

Type
loss
Manifestation
family
Exon
1
Pedigree 1 - Camilot et al.
Pedigree 2 - Labo-Abeal
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 (Camilot et al.):
III/1, II/2: heterozygous






Family 2 - Pedigree 2 (Lado-Abeal et al.)
II/3, I/2 heterozygous for E34K

II/4, III/1 and III/2:
heterozygous: GNASc.750_751insA:
insertion at exon 10 (p.N250K) and frameshift stop a codon 285

III/1: compound heterozygous E34K/GNASMut

brother and parents of II/4: wildtype (not shown) 
Clinical Features:
Family 1 - Pedigree 1 (Camilot et al.):
III/1: hypothyroid newborn, second child of 2 non-consanguineous parents
II/2: euthyroid
I/2: hypothyroidism
III/1: seizure-like convulsion at 4 days
normal thyroid
3yr: operation for monolateral cryptorchism, normal growth at 7yrs
eutopic thyroid gland, Ab negative

Family 2 - Pedigree 2 (Lado-Abeal et al.):
II/3: propositus diagnosis at 18mo: macroglossia, listlessness, severe constipation, normal development
I/2: mother: hypothyroidism secondary to radio-iodine treatment for Grave’s disease
II/4: wife of propositus, euthyroid, heterotopic ossifications in forearms affecting medial nerves
III/1: daughter: euthyroid hyperthyrotropinaemia, decreased Tc99m uptake: Pseudohypoparathyroidism (PHP1a), oral Calcium and D3 treatment
III/2 second daughter: temporomandibular joint ankylosis, euthyroid hyperthyrotropinaemia, decreased Tc99m uptake, Pseudohypoparathyroidism (PHP1a), oral Calcium and D3 treatment, mild growth retardation 
Treatment:
L-T4
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2
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:
Camilot et al.
Clin Endocrinol (Oxf) 63:146-151.
Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes.
2005