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- Title
Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants.
- Authors
Hosoe, Jun; Kawashima-Sonoyama, Yuki; Miya, Fuyuki; Kadowaki, Hiroko; Suzuki, Ken; Kato, Takashi; Matsuzawa, Fumiko; Aikawa, Sei-Ichi; Okada, Yukinori; Tsunoda, Tatsuhiko; Hanaki, Keiichi; Kanzaki, Susumu; Shojima, Nobuhiro; Yamauchi, Toshimasa; Kadowaki, Takashi
- Abstract
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.
- Subjects
MISSENSE mutation; GENETIC variation; INSULIN resistance; STRUCTURAL bioinformatics; INSULIN receptors; STATURE; HAMSTERS; RODENTS; RESEARCH; GENETIC mutation; ANIMAL experimentation; RESEARCH methodology; CELL receptors; RETROSPECTIVE studies; MEDICAL cooperation; EVALUATION research; COMPARATIVE studies; GENETIC techniques; ANTIGENS; GROWTH disorders; PHENOTYPES
- Publication
Diabetes, 2021, Vol 70, Issue 8, p1874
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db20-1145