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Functional studies of new TSH receptor (TSHr) mutations identified in patients affected by hypothyroidism or isolated

Giuseppina De Marco1, Patrizia Agretti, Marta Camilot

  • 1Dipartimento di Endocrinologia e Metabolismo, Centro Eccellenza AmbiSEN, Università di Pisa, Pisa, Italy.

Clinical Endocrinology
|August 30, 2008
PubMed
Abstract

Insights

Several TSH receptor (TSHr) variants identified in children with hypothyroidism cause functional abnormalities. However, the P27T variant appears to be a benign polymorphism, not contributing to the condition.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) can arise from genetic factors affecting thyroid hormone production.
  • Thyroid-stimulating hormone receptor (TSHr) is crucial for thyroid function, and its variants may lead to endocrine disorders.
  • Recent identification of novel TSHr variants in children with CH/SH warrants functional characterization.

Purpose of the Study:

  • To investigate the functional impact of newly identified TSHr variants (P27T, E34K, R46P, D403N, W488R, M527T) in pediatric hypothyroidism.
  • To determine if these TSHr variants affect receptor signaling and TSH binding.

Main Methods:

  • TSHr variants were generated using site-directed mutagenesis.
  • Wild-type and mutant TSHr were expressed in COS cells.
  • Functional assays included cAMP production measurement, (125)I-TSH binding assays, and microchip flow cytometry.

Main Results:

  • Mutants D403N and M527T exhibited reduced cAMP response to bovine TSH (bTSH) and decreased TSH binding.
  • Mutants R46P and W488R showed no cAMP response or TSH binding, indicating complete loss of function.
  • Mutant E34K displayed significantly reduced cAMP response and TSH binding, while P27T showed a diminished cAMP response only at high bTSH doses and reduced TSH binding.

Conclusions:

  • TSHr variants E34K, D403N, M527T, R46P, and W488R are associated with functional receptor abnormalities contributing to the observed phenotype in CH/SH.
  • The P27T TSHr variant is unlikely to play a functional role in CH pathogenesis and may represent a polymorphism.

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