Article

Identification of TSH receptor mutations in three families with resistance to TSH.

Dipartimento di Endocrinologia e Metabolismo, Centro Eccellenza AmbiSEN, Università di Pisa, Pisa, Italy.
Clinical Endocrinology (impact factor: 3.17). 12/2007; 67(5):712-8. DOI:10.1111/j.1365-2265.2007.02950.x pp.712-8
Source: PubMed

ABSTRACT Genetic analysis of the TSH receptor gene in seven subjects with subclinical hypothyroidism (SH), in whom the diagnosis of autoimmune thyroid disease had been excluded by laboratory and instrumental techniques currently available.
Three families where different members (2 children and 5 adults) affected by SH were studied. GENETIC ANALYSIS: Genomic DNA was extracted from peripheral lymphocytes and the entire coding sequence of the TSHr gene was sequenced. pSVL-TSHr construct harbouring a Q8fsX62 insertion was obtained by site-directed mutagenesis. COS-7 cells transfected with wild-type and mutant receptor were used for binding studies, flow cytometry, and cyclic AMP (cAMP) determination.
A four base pair (bp) duplication in position 41 (41TGCAins), leading to a premature stop of translation at codon 62 (Q8fsX62), was found to be heterozygous in the proband, the father and the sister in Family 1. In Family 2 the proband and the sister were heterozygous for the mutation D410N. In Family 3 the proband and the father were heterozygous for the mutation P162A. After transfection in COS-7 cells, the mutant receptor Q8fsX62 displayed a low expression at the cell surface, and a reduced response to bovine TSH (bTSH) in terms of cAMP production.
We identified TSH receptor mutations in seven members of three families with subclinical hypothyroidism.

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    Article: Type Ib pseudohypoparathyroidism associated with thrombocytopenia and possibly resistance to TSH
    Raluca Trifanescu, F Alexiu, Anda Dumitrascu, M Coculescu
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    ABSTRACT: An 18 years old, tall man presented for circumoral numbness, paresthesias, and hypocalcaemia, without carpopedal spasm or seizures. Previous medical history revealed bilateral cataract and osseous cysts on limbs at the age of 12. Hypocalcaemia resistant to calcium treatment and mild increased TSH levels were present. At diagnosis, we noticed a normal phenotype with tall stature, moderate hypocalcaemia (5.8 mg/dL), hyperphosphatemia (5.08 mg/dL) and significantly higher than normal intact parathormone (PTH) levels (518 pg/mL), in the presence of normal serum levels of 25-hydroxy vitamin D (53.56 ng/mL). The mother and the family members have been found in good health. All these data strongly suggested sporadic pseudohypoparathyroidism type Ib (PHP-Ib), but with some features of PHP -type Ia, like the osseous cysts. We were not able to perform molecular genetic tests. The nearly complete recovery of clinical and biochemical signs (normalization of PTH, calcaemia, phosphatemia, and a normal DXA osteodensitometry) after 2 years of chronic treatment with activated 1,25-dihydroxycholecalciferol (2.00-0.75 µg/day) indirectly, but strongly confirmed the diagnosis of pseudohypoparathyroidism. The patient may have resistance to TSH evidenced by high TSH (range 4.8-7.5 mIU/L), with normal thyroid hormone levels, absence of goiter and normal TPO antibodies. The TRH test (400 µg i.v.) showed a response of TSH, and also of serum thyroxine and triiodothyronine in a range that did not clarify the diagnosis. This association of the resistance to TSH with type Ib PHP was relatively recently reported by two groups (17,20) and before them it was reported only in PHP-Ia. Our patient also showed mild thrombocytopenia, with normal bleeding time, indicating also a possible Gsα deficiency in platelets. In conclusion, our patient with sporadic pseudohypoparathyroidism without clinical phenotype of Albright hereditary osteodystrophy is highly suggestive for the type Ib PHP. A possible resistance to TSH and thrombocytopenia associated are features related to the genetic mechanisms found also in type Ia PHP. It is tempting to suggest that this case is one of the new variants of pseudohypoparathyroidism-Ib, recently reported. Key words: pseudohypoparathyroidism type Ib, pseudohypoparathyroidism type Ia, resistance to TSH, hypocalcaemia.
    Acta Endocrinologica (Buc). 01/2008;
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Keywords

bovine TSH
 
cAMP production
 
cell surface
 
COS-7 cells
 
COS-7 cells transfected
 
entire coding sequence
 
Family 2
 
four base pair
 
Genetic analysis
 
Genomic DNA
 
instrumental techniques
 
mutant receptor
 
mutant receptor Q8fsX62
 
mutation P162A
 
pSVL-TSHr
 
reduced response
 
subclinical hypothyroidism
 
TSH receptor gene
 
TSH receptor mutations
 
TSHr gene