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Abstract：
The objectives of the present study were to identify CYP4V2 genetic variants and characterize their functional consequences. A total of 26CYP4V2 genetic variants were identified, including seven novel variants in 60 randomly selected healthy subjects. Six protein-coding variants were studied, including three novel variants (L22V, R287T, and G410C) and three previously reported variants (R36S, Q259K, and H331P). The cDNA sequences encoding each amino acid variant and the wild-type CYP4V2 protein were cloned into the pcDNA/PDEST40 expression vector and transfected into eukaryotic 293T cells for overexpression of the CYP4V2 coding variants. CYP4V2 H331P and CYP4V2 G410C exhibited significant decreases in activity for lauric acid oxidation (20-30% of wild-type activity), when compared to the wildtype, which was correlated with low expression of CYP4V2 H331P and G410C substituted proteins. The other four CYP4V2 amino variants were comparable to wild-type CYP4V2 for lauric acid metabolism. The CYP4V2 H331P and G410C substitutions were predicted to cause a structural change through in silico analysis. In conclusion, the present study provides functional information about CYP4V2 genetic variants. These findings will be valuable for interpreting individual variations in phenotypes associated with CYP4V2 function in the clinical setting.
摘要：
本研究的目的是鉴定CYP4V2遗传变体并表征其功能后果。共鉴定出26CYP4V2遗传变异体，包括60名随机选择的健康受试者中的7个新变体。研究了六种蛋白质编码变体，包括三个新颖的变体(L22V，R287T,和G410C）和三个先前报道的变体（R36S，Q259K,和H331P）。将编码每个氨基酸变体和野生型CYP4V2蛋白的cDNA序列克隆到pcDNA/PDEST40表达载体中,并转染到真核293T细胞中,用于过表达CYP4V2编码变体。CYP4V2H331P和CYP4V2G410C表现出月桂酸氧化活性的显着降低（野生型活性的20-30％），当与野生型相比时，这与CYP4V2H331P和G410C替代蛋白的低表达有关。其他四种CYP4V2氨基变体在月桂酸代谢方面与野生型CYP4V2相当。通过计算机模拟分析预测CYP4V2H331P和G410C取代会引起结构变化。总之,本研究提供了CYP4V2遗传变异的功能信息.这些发现对于在临床环境中解释与CYP4V2功能相关的表型的个体差异将是有价值的。
