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

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posted on 01.06.2021, 20:08 by 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
We previously reported that 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.


This study received a grant-in-aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT) (grant 19K16534 to J.H.).