Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants

Jun Hosoe, Yuki Kawashima-Sonoyama, Fuyuki Miya, Hiroko Kadowaki, Ken Suzuki, Takashi Kato, Fumiko Matsuzawa, Sei Ichi Aikawa, Yukinori Okada, Tatsuhiko Tsunoda, Keiichi Hanaki, Susumu Kanzaki, Nobuhiro Shojima, Toshimasa Yamauchi, Takashi Kadowaki

研究成果: Article査読

抄録

We previously reported genotype-phenotype correlations in 12 missense variants causing severe insulin resistance, located in the second and third fibronectin type III (FnIII) domains of the insulin receptor (INSR), containing the α-β cleavage and part of insulin-binding sites. This study aimed to identify genotype-phenotype correlations in FnIII domain variants of IGF1R, a structurally related homolog of INSR, which may be associated with growth retardation, using the recently reported crystal structures of IGF1R. A structural bioinformatics analysis of five previously reported disease-associated heterozygous missense variants and a likely benign variant in the FnIII domains of IGF1R predicted that the disease-associated variants would severely impair the hydrophobic core formation and stability of the FnIII domains or affect the α-β cleavage site, while the likely benign variant would not affect the folding of the domains. A functional analysis of these variants in CHO cells showed impaired receptor processing and autophosphorylation in cells expressing the disease-associated variants but not in those expressing the wild-type form or the likely benign variant. These results demonstrated genotype-phenotype correlations in the FnIII domain variants of IGF1R, which are presumably consistent with those of INSR and would help in the early diagnosis of patients with disease-associated IGF1R variants.

本文言語English
ページ(範囲)1874-1884
ページ数11
ジャーナルDiabetes
70
8
DOI
出版ステータスPublished - 2021 8月 1
外部発表はい

ASJC Scopus subject areas

  • 内科学
  • 内分泌学、糖尿病および代謝内科学

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