Greene Sunny, Talbert Mackenzie L, Frost F Graeme, Zerfas Patricia M, Springer Danielle, Noguchi Audrey, Morimoto Marie, Maynard Dawn, Garrett Lisa, Elliot Gene, Traver Maria, Yarnell David, Leoyklang Petcharat, Burke John D, Nicoli Elena-Raluca, Gahl William A, Introne Wendy J, Malicdan May Christine V
Human Biochemical Genetics Section, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
National Institutes of Health Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Commun Biol. 2025 Jul 18;8(1):1064. doi: 10.1038/s42003-025-08482-1.
Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder caused by pathogenic variants in the lysosomal trafficking regulator (LYST) gene and characterized by significant immunological and neurological impairment. Current mouse models do not replicate the early-onset neurological symptoms of patients. We develop and characterize a CHS model lacking the Lyst gene (ΔLYST-B6) using CRISPR-Cas9. The ΔLYST-B6 mouse exhibits key CHS features, including partial oculocutaneous albinism, prolonged bleeding, and enlarged intracellular granules. Molecular analyses confirm LYST deficiency, with reduced Lyst mRNA and protein levels across various tissues. Histological examination reveals progressive cerebellar Purkinje cell loss and axonal degeneration in peripheral nerves. Importantly, the ΔLYST-B6 show significant neurological impairment by 6 months of age. Lipidomic and transcriptomic analyses highlight increased proinflammatory lipid levels and immune signaling, suggesting neuroinflammation in CHS pathology. The ΔLYST-B6 mouse provides a valuable tool for studying the underlying mechanisms of CHS-associated neurodegeneration and for developing potential therapeutic strategies.
切迪阿克-希加什综合征（CHS）是一种罕见的常染色体隐性疾病，由溶酶体运输调节因子（LYST）基因的致病性变异引起，其特征是严重的免疫和神经功能损害。目前的小鼠模型无法复制患者的早发性神经症状。我们使用CRISPR-Cas9技术开发并鉴定了一种缺乏Lyst基因的CHS模型（ΔLYST-B6）。ΔLYST-B6小鼠表现出关键的CHS特征，包括部分眼皮肤白化病、出血时间延长和细胞内颗粒增大。分子分析证实了LYST的缺陷，不同组织中的Lyst mRNA和蛋白质水平均降低。组织学检查显示小脑浦肯野细胞逐渐丢失，外周神经出现轴突退化。重要的是，ΔLYST-B6小鼠在6个月大时表现出明显的神经功能损害。脂质组学和转录组学分析突出了促炎脂质水平和免疫信号的增加，提示CHS病理过程中存在神经炎症。ΔLYST-B6小鼠为研究CHS相关神经退行性变的潜在机制和开发潜在治疗策略提供了有价值的工具。
