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

研究成果: Article

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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.

元の言語English
ページ(範囲)123-130
ページ数8
ジャーナルClinical Pediatric Endocrinology
27
発行部数3
DOI
出版物ステータスPublished - 2018 1 1

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Thyrotropin Receptors
Mutation
Congenital Hypothyroidism
Phenotype
Missense Mutation
Thyroxine
Iodine
Signal Transduction
Thyroid Gland
Genotype
Serum
Genes

ASJC Scopus subject areas

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

これを引用

Identification of compound heterozygous TSHR mutations (R109Q and R450H) in a patient with nonclassic TSH resistance and functional characterization of the mutant receptors. / Sugisawa, Chiho; Abe, Kiyomi; Sunaga, Yuka; Taniyama, Matsuo; Hasegawa, Tomonobu; Narumi, Satoshi.

:: Clinical Pediatric Endocrinology, 巻 27, 番号 3, 01.01.2018, p. 123-130.

研究成果: Article

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AU - Narumi, Satoshi

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AB - 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.

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