One novel and two recurrent THRB mutations associated with resistance to thyroid hormone: Structure-based computational mutation prediction

Satoshi Narumi, Hideo Cho, Izumi Tamada, Yuki Kozu, Takayoshi Tsuchiya, Toshiro Nagai, Tomonobu Hasegawa

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Inactivating mutations of THRB, which encodes the thyroid hormone receptor β (TRβ), cause resistance to thyroid hormone (RTH; OMIM 190160). To date, more than 100 THRB mutations have been reported among RTH patients. Most mutations substitute a single amino-acid residue in the ligand-binding domain. In this report, we describe clinical and molecular findings of three families with RTH. Three families harbored one novel (p.I431M) and two recurrent (p.R320H and p.R383C) THRB mutations. To examine the pathogenicity of identified mutations, we introduced a novel computational mutation prediction method based on three-dimensional structure data of TRβ-T3 complex. First, to define the accuracy of our prediction system, we evaluated ten previously reported 'positive control' mutations, as well as 30 seemingly benign sequence variations observed among vertebral species as 'negative controls'. We found that our system had a sensitivity of 80% and a specificity of 93%. We then analyzed three mutations detected in the present study and found that all three mutations are predicted to be deleterious. Our data suggest that our structure-based prediction system would be a prompt, inexpensive and feasible method for evaluating the pathogenicity of missense THRB mutations.

Original languageEnglish
Pages (from-to)91-99
Number of pages9
Journalclinical pediatric endocrinology
Volume19
Issue number4
DOIs
Publication statusPublished - 2010 Dec 1

Keywords

  • Computational biology
  • Genetics
  • Mutation
  • Thyroid hormone receptor beta
  • Thyroid hormone resistance syndrome

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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