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

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 id...

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Veröffentlicht in:Diabetes (New York, N.Y.) N.Y.), 2021-08, Vol.70 (8), p.1874-1884
Hauptverfasser: 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
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Sprache:eng
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Zusammenfassung: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.
ISSN:0012-1797
1939-327X
DOI:10.2337/db20-1145