TY - JOUR
T1 - Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants
AU - Hosoe, Jun
AU - Kawashima-Sonoyama, Yuki
AU - Miya, Fuyuki
AU - Kadowaki, Hiroko
AU - Suzuki, Ken
AU - Kato, Takashi
AU - Matsuzawa, Fumiko
AU - Aikawa, Sei Ichi
AU - Okada, Yukinori
AU - Tsunoda, Tatsuhiko
AU - Hanaki, Keiichi
AU - Kanzaki, Susumu
AU - Shojima, Nobuhiro
AU - Yamauchi, Toshimasa
AU - Kadowaki, Takashi
N1 - Funding Information:
This study received a Grant-in-Aid for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant 19K16534 to J.H.).
Publisher Copyright:
© 2021 by the American Diabetes Association.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
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U2 - 10.2337/DB20-1145
DO - 10.2337/DB20-1145
M3 - Article
C2 - 34074726
AN - SCOPUS:85114707717
VL - 70
SP - 1874
EP - 1884
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 8
ER -