Details Of Published TSH Receptor Mutation

Met 463 Val

c.1387A>G

Constitutively Activating TSH Receptor Mutation

Type
gain
Manifestation
family
Exon
10
Pedigree 1 - F├╝hrer et al.
Pedigree 2 - Lee et al.
Pedigree 3 - Arturi et al.
Pedigree 4 - Ferrara et al.
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
hereditary occurrence in 4 non-related families

Family 1: "Cardiff family" - Pedigree 1: Fuhrer et al.

Family 2: Pedigree 2: Lee et al.

Family 3: Pedigree 3: Arturi et al.
Note:
Blue marked individuals are identical (I/1 is married twice)

Family 4: Pedigree 4: Ferrara et al. 
Clinical Features:
Family 1: "Cardiff family" - Pedigree 1 (Fuhrer et al.):
diagnosis:
P1/VI/4: 4.9yr (index patient)
P1/VI/1: 7yr, diffuse goiter
P1/VI/2: 5yr
P1/VI/3: 2yr
P1/V/1: 9yr
P1/V/2: 21yr
P1/V/5: 13yr
P1/IV/1: 20yr

P1/V/2, P1/VI/1, P1/VI/4:
borderline TG-antibodies
P1/V/1, P1/V/2:
ectopic pregnancies
P1/IV/1:
2 stillbirth during thyrotoxicosis


Family 2 - Pedigree 2 (Lee et al.):
diagnosis:
P2/IV/2: 5.5yr (index patient)
P2/IV/3: 2.7yr (index patient)
P2/IV/1: 7yr
P2/IV/4: 5yr
P2/III/1: 11yr
P2/III/3: 20yr
P2/III/9: 13yr
P2/II/1: hyperthyroid
P2/I/1: thyrotoxicosis


Family 3 - Family 3 (Arturi et al.):
diagnosis:
P3/III/1: 14yr
P3/III/2: 17yr
P3/III/3: 18yr
P3/IV/1: 12yr
P3/IV/4: 12yr
P3/IV/5: 14yr
P3/IV/6: 14yr
P3/IV/7: 11yr

goiter: P3/III/1,2,3, P3/IV/1,4,5,6,7
hyperthyroid individuals without mutation: P3/I/1, P3/II/1,2,4, P3/IV/2


Family 4 - Pedigree 4 (Ferrara et al.):
diagnosis:
P4/III/1: 8yr, goiter
P4/II/2: 18yr, goiter
P4/II/1: 27yr, goiter
P4/I/2: 30yr, goiter

P4/III/1: prominent eyes

*based on 1 hot nodule investigated by Paloz-Paz et al. 2008
and 4 activating familial germline mutations investigated by Fuhrer et al. 200, Lee et al. 2002, Arturi et al. 2002 and Ferrara et al. 2007 
Treatment:
Family 1: "Cardiff family" - Pedigree 1 (Fuhrer et al.):
P1/VI/1, P1/VI/2, P1/VI/3:
antithyroid medication
P1/VI/4: antithyroid medication and L-thyroxine, euthyroid
P1/V/1: partial TE, antithyroid drugs since, relapse of hyperthyroidism
P1/V/2: subtotal TE, L-thyroxine treatment
P1/V/5: antithyroid drugs
P1/IV/1: partial TE at 26yr,
euthyroid since








Family 2 (Lee et al.):
P2/IV/1, P2/IV/2, P2/IV/3, P2/IV/4, P2/III/9: antithyroid drugs
P2/III/1: STE at 19yr, antithyroid drugs
P2/III/3: TE, L-T4
P2/II/1: STE at 26yr







Family 3 (Arturi et al.):
P3/III/1: partial TE at 29yr, relapse at 46yr, radio-iodine therapy (8mCi), euthyroid under L-T4
P3/III/2: partial TE at 40yr, relapse at 52yr, radio-iodine therapy (10mCi), antithyroid drugs since
P3/III/3: radio-iodine therapy (10mCi)IV/4: partial TE at 19yr, relapse at 26yr, antithyroid drugs since
P3/IV/6, P3/IV/7: antithyroid drugs
P3/IV//: partial TE at 15yr, relapseat 15.5yr, antithyroid drugs since







Family 4 (Ferrara et al.):
P4/III/1, I/2: antithyroid drugs
P4/II/2: antithyroid drugs ineffective, near total TE at 35yr, euthyroid thereafter
P4/II/1: antithyroid drugs, total TE at 40yr, L-T4
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
2.0-3.3
1.8
1.0
n.d.
-
0.6
4
13.5+/-0.7
1,5
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:
Fuhrer et al.
Thyroid 10: 1035-1041
Novel TSHR Germline Mutation (Met463Val) Masquerading as Graves' Disease in a Large Welsh Kindred with Hyperthyroidism
2000
Reference 2:
Lee et al.
J Pediatr Endocrinol Metab. 15: 211-5
An activating mutation of the thyrotropin receptor gene in hereditary non-autoimmune hyperthyroidism.
2002
Reference 3:
Arturi et al.
J Endocrinol Invest. 25: 696-701
Similarities and differences in the phenotype of members of an Italian family with hereditary non-autoimmune hyperthyroidism associated with an activating TSH receptor germline mutation.
2002
Reference 4:
Ferrara et al.
Thyroid 17: 677-80
A new case of familial nonautoimmune hyperthyroidism caused by the M463V mutation in the TSH receptor with anticipation of the disease across generations: a possible role of iodine supplementation.
2007
Reference 5:
Mueller et al.
Thyroid. 19(7):765-73
Cases of borderline in vitro constitutive thyrotropin receptor activity: how to decide whether a thyrotropin receptor mutation is constitutively active or not?
2009