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Structural insights revealed by two novel THRB mutations.

Ludmilla Ferreira Cardoso1, Maria Clara de Carvalho Melo2, Mirian Hideco Takahashi3

  • 1Department of Internal Medicine, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.

Endocrine
|January 6, 2020
PubMed
Summary

Two novel mutations in the thyroid hormone receptor beta gene (THRB) cause resistance to thyroid hormone (RTH). The L346R mutation results in greater impairment than N331H due to significant structural changes in the receptor

Keywords:
CrystallographyL346R THRB mutationN331H THRB mutationResistance to thyroid hormone betaStructural analysisThyrotroph T4 resistance index

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Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • Resistance to thyroid hormone (RTH) is an inheritable condition affecting thyroid hormone sensitivity.
  • Mutations in the thyroid hormone receptor beta gene (THRB) cause RTH, presenting with diverse phenotypes and unclear pathophysiology.
  • Understanding these mutations is crucial for elucidating RTH mechanisms.

Purpose of the Study:

  • To investigate the functional and structural impact of two novel THRB mutations, N331H and L346R.
  • To elucidate the molecular mechanisms underlying impaired thyroid hormone signaling caused by these mutations.
  • To correlate mutation characteristics with the severity of thyrotrophic resistance.

Main Methods:

  • Reproduced N331H and L346R THRB mutations in vitro.
  • Assessed gene transactivation using dual-luciferase reporter assays.
  • Performed molecular modeling for structural analysis of the ligand-binding cavity (LBC).
  • Measured serum TSH and FT4 levels to evaluate thyrotrophic resistance.

Main Results:

  • Both N331H and L346R mutations impaired gene transactivation, with L346R showing more severe effects.
  • Molecular modeling revealed distinct structural impacts: N331H affected hydrogen bond strength in the LBC, while L346R altered LBC hydrophobicity and volume.
  • Hormonal analyses confirmed greater thyrotrophic resistance in L346R mutants compared to N331H.

Conclusions:

  • Novel THRB mutations N331H and L346R cause resistance to thyroid hormone through deleterious structural changes in the LBC.
  • The severity of functional damage is influenced not only by mutation location but also by the specific amino acid exchange.
  • These findings provide a rational understanding of RTH pathogenesis and the role of receptor structure in hormone resistance.