Identification of compound heterozygous TSHR mutations (R109Q and R450H) in a patient with nonclassic TSH resistance and functional characterization of the mutant receptors

Chiho Sugisawa, Kiyomi Abe, Yuka Sunaga, Matsuo Taniyama, Tomonobu Hasegawa, Satoshi Narumi

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Genetic defects of the TSH receptor (TSHR) signaling pathway cause a form of congenital hypothyroidism (CH) known as TSH resistance. Consistent with the physiological understanding that thyroidal iodine uptake is up-regulated by TSHR signaling, most patients with TSH resistance have low to normal thyroidal 123I uptake representing the classic TSH resistance. However, paradoxically high 123I uptake was reported in four molecularly-confirmed patients indicating nonclassic TSH resistance. Here, we report the fifth patient with the nonclassic phenotype. He was a 12-yr-old CH patient and treated with levothyroxine. At the age 11 yr, he showed slightly small thyroid gland and elevated thyroidal 123I uptake. Genetic analysis showed that he was compound heterozygous for two known missense mutations (Arg109Gln and Arg450His) in the TSHR gene. Further, the signal transduction of Arg109Gln-TSHR was defective in both Gs-and Gq-coupled pathways, while Arg450His-TSHR showed Gq-dominant defect. 123I uptake was evaluated earlier in 16 patients with TSH resistance, and a correlation between TSH levels and 123I uptake was shown in patients with specific genotypes (Arg450His or Leu653Val). Collectively, we have re-confirmed that the emergence of the nonclassic phenotype requires two factors: mutant TSHR with Gq-dominant coupling defect and relatively high levels of serum TSH.

Original languageEnglish
Pages (from-to)123-130
Number of pages8
JournalClinical Pediatric Endocrinology
Issue number3
Publication statusPublished - 2018 Jan 1



  • Congenital hypothyroidism
  • Genetics
  • Mutation
  • TSH receptor
  • TSH resistance

ASJC Scopus subject areas

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

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