Details Of Published TSH Receptor Mutation

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Pro 162 Ala

c.484C>G

Inactivating TSH Receptor Mutation

Type

loss

Manifestation

family

Exon

Pedigree 1 - Sunthornthepvarakui et al.

Pedigree 2 - De Roux et al.

Pedigree 3 - Tonacchera et al. 2001

Pedigree 4 - Tonacchera et al. 2007

Pedigree 5 - Tonacchera et al. 2004

Pedigree 6 - Nicoletti et al.

Pedigree 7 - Alberti et al.

Labadi et al.

Legend:

Male

Female

Unknown

Deceased

Mutation

Wild-Type

Heterozygous

Compound Heterozygous

Homozygous

Hypothyroid

Hypoplastic Gland + Hypothyroid

Index Patient

Molecular Characteristics:

Family 1 - pedigree 1 (Sunthornthepvaraku et al.):
I/1: Ile167Asn
I/2: Pro162Ala/Pro52Thr
II/1-3: Pro162Ala/Ile167Asn
compound heterozygous
polymorphism Pro52Thr in I/2

Family 2 - pedigree 2 (de Roux et al.):
I/1: Pro162Ala
I/2: Pro162Ala (consanguinous)
II/3: Pro162Ala homozygous
II/1: Pierre-Robin syndrome
II/2: Down's syndrome

Family 3 - pedigree 3 (Tonacchera et al. 2001):
I/1: polymorphism Pro52Thr
I/2: Pro162Ala/Pro162Ala
II/1: Pro162Ala
compound heterozygous
polymorphism Pro52Thr

Family 4 - pedigree 4 (Tonacchera et al. 2007):
proband and father: heterozygous for P162A, and P52T polymorphism
two children: wild type

Family 5 - pedigree 5 (Tonacchera et al. 2004):
III/2 proband: homozygous, consanguineous parents
II/2: mother heterozygous
IV/2: son: heterozygous
II/1 and II/3, II/3 and II/4: consanguinous parents

Family 6 - pedigree 6 (Nicoletti et al.):
propositus and father heteroz.

Family 7 - pedigree 7 (Alberti et al.):
I/1: Cys600Arg
I/2: P162Ala
II/1: Cys600Arg/P162Ala compound heterozygous
II/2: Pro162Ala

Family 8 - pedigree 8 (Camilot et al.):
son: homozygous
sister, parents heterozygous for P162A
1 non related child heterozygous

Family 9: P162S/R450H

Clinical Features:

Family 1 - pedigree 1 (Sunthornthepvarakui et al.):
diagnosis:
II/1: 4yr
II/2: neonatal
II/3: neonatal, euthyroid hyperthyrotropinaemia, normal scintiscan
I/1 and I/2: borderline TSH levels

Family 2 - pedigree 2 (de Roux et al.):
diagnosis:
II/3: neonatal, euthyroid hyperthyrotropinaemia, normal gland on 123-I scan

Family 3 - pedigree 3 (Tonacchera et al. 2001):
diagnosis:
I/2: 47yr, euthyroid hyperthyrotropinaemia, normal gland on ultrasound development of hypothyroidism with concomittant autoimmune thyroid disease
II/1: borderline TSH levels

Family 4 - pedigree 4 (Tonacchera et al. 2007):
II/1: 38yr male, hyperthyrotropinaemia, Ab negative
thyroid: no goiter, normal ultrasound pattern
I/1: TSH elevated
III/1, III/2 normal thyroid function

Family 5 - pedigree 5 (Tonacchera et al. 2004):
prop: 47yr woman, neck discomfort, isolated hyperthyrotropinemia, no sings of hypothyroidism
mother: TSH elevated
son: euthyroid 23yrs, basal TSH elevated
III/3 4 sister and brother: normal thyroid tests
IV/2 daughter of the sister: TSH elevated
IV/3: normal, daughter: V/1: TSH elevated, TPOAb and TgAb pos. chron. autoimmune thyroiditis

Family 6 - pedigree 6 (Nicoletti et al.):
prop: hypoplastic thyroid, growth retardation

Family 7 - pedigree 7 (Alberti et al.):
diagnosis:
II/1: 25yr, euthyroid hyperthyrotropinaemia, hypoplastic thyroid gland, 1 brother and parents with borderline TSH levels

Family 8 - pedigree 8 (Camilot et al.:)
son: hypothyroid newborn, eutopic thyroid gland, Ab negative, sister subclinical hypothyrodism
1 non related child with subclinical hypothyrodism, heterozygous

Family 9: Vigone et al. P162A siblings with heterozygous mutation, no parental data thus familial assumed

Treatment:

L-thyroxine

Functional Characteristics:

cAMP
(basal)

cAMP
(TSH)

IP
(basal)

IP
(TSH)

TSH-Binding

Cell Surface Expression

Prevalence

LRA

Ref

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:

Sunthornthepvarakui et al.

N. Engl. J. Med. 332: 155-157

Brief report: resistance to thyrotropin caused by mutations in the thyrotropin-receptor gene

1995

Abstract In Medline Available

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

Abstract In Medline Available

Reference 3:

Tonacchera et al.

J. Clin. Endocrinol. Metab. 86: 4543-4546

Thyroid Resistance to TSH Complicated by Autoimmune Thyroiditis

2001

Abstract In Medline Available

Reference 4:

Costagliola et al.

Thyroid 9: 995-1000

Structure-function relationships of two loss-of-function mutations of the thyrotropin receptor gene

1999

Abstract In Medline Available

Reference 5:

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

Abstract In Medline Available

Reference 6:

Camilot et al.

Clin Endocrinol (Oxf) 63:146-151.

Thyrotropin receptor gene mutations and TSH resistance: variable expressivity in the heterozygotes.

2005

Abstract In Medline Available

Reference 7:

Cangul et al.

Clin Endocrinol (Oxf) 73:671-677.

Novel TSHR mutations in consanguineous families with congenital nongoitrous hypothyroidism.