이선호 (한국기초과학지원연구원)

황금숙 (한국기초과학지원연구원)

이선호 (한국기초과학지원연구원)

정영애 (한국기초과학지원연구원)

한기훈 (고려대학교)

황금숙 (한국기초과학지원연구원)

West syndrome is a form of infantile-onset epilepsy characterized by high mortality and a persistent risk of seizures. Recent studies have identified the Cyfip2 p.Arg87Cys mutation as a causative factor for seizures and abnormal lipid accumulation in the brain. In this study, lipidomic profiling was conducted to investigate differences in lipid composition between Cyfip2 knock-in (KI) and wild-type (WT) mice across two distinct brain regions: the hippocampus and cortex. Lipid profiles from postnatal week 28 mice were analyzed using liquid chromatography-trapped ion mobility spectrometry-time-of-flight mass spectrometry (LC-TIMS-TOF MS). Multivariate analysis revealed clear genotype-dependent separation in principal component analysis (PCA) score plots. In total, 745 lipid species across 27 classes within five major categories were identified. Among them, glycerophospholipid-related species, which are key structural components of membranes and are involved in various cellular functions, such as lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylglycerol (PG), were consistently altered in both the hippocampus and cortex, reflecting the effects of the Cyfip2 knock-in mutation. Significant alterations were also observed in ether lipids, including ether-linked LPE (LPE-O), PC (PC-O), diacylglycerol (DG-O), and triacylglycerol (TG-O). Region-specific lipid alterations were additionally detected as a result of the knock-in mutation. In the hippocampus, neutral lipids such as cholesterol ester (CE), monogalactosyldiacylglycerol (MGDG), and triacylglycerol (TG), which are associated with lipid droplet formation, were differentially regulated. In contrast, the cortex showed distinct alterations in hexosylceramide-related species, including acylhexosylceramide (AHexCer), hexosylceramide (HexCer), and sulfatide (SHexCer), which are involved in signal transduction and neurophysiological regulation. These findings suggest that the Cyfip2 mutation leads to region-specific lipid alterations in the brain, which may contribute to the pathophysiology and heterogeneity of West syndrome.​