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

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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 a-b cleavage and part of insu-lin-binding sites. This study aimed to identify geno-type-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 hydro-phobic core formation and stability of the FnIII domains or affect the a-b 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 autophosphor-ylation 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.

Original languageEnglish
Pages (from-to)1874-1884
Number of pages11
Issue number8
Publication statusPublished - 2021 Aug
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism


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