Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants
Genotype-Structure-Phenotype Correlations of Disease-Associated IGF1R Variants and Similarities to Those of INSR Variants
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DOI：
10.2337/db20-1145
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发表时间：
2021-08-01
期刊：
影响因子：
7.7
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Hosoe, Jun;Kawashima-Sonoyama, Yuki;Kadowaki, Takashi
我们之前报道了导致严重胰岛素抵抗的 12 种错义变异的基因型-表型相关性，这些错义变异位于胰岛素受体 (INSR) 的第二和第三纤连蛋白 III 型 (FnIII) 结构域，包含 α-β 裂解和部分胰岛素结合位点。本研究旨在利用最近报道的 IGF1R 晶体结构，确定 IGF1R（INSR 的结构相关同源物）FnIII 结构域变体的基因型-表型相关性，这可能与生长迟缓相关。对先前报道的五种与疾病相关的杂合错义变体和 IGF1R FnIII 结构域中可能的良性变体进行的结构生物信息学分析预测，与疾病相关的变体将严重损害 FnIII 结构域的疏水核心形成和稳定性或影响 α-β 切割位点，而可能的良性变体不会影响结构域的折叠。对 CHO 细胞中这些变体的功能分析显示，在表达疾病相关变体的细胞中，受体加工和自磷酸化受损，但在表达野生型形式或可能良性变体的细胞中则没有。这些结果证明了 IGF1R FnIII 结构域变体的基因型-表型相关性，这可能与 INSR 的基因型-表型相关性一致，并将有助于疾病相关 IGF1R 变体患者的早期诊断。
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 alpha-beta 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 alpha-beta 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.