Division of Neurobiology and Anatomy, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, Japan.
Department of Animal Model Development, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Int J Mol Sci. 2024 Jul 16;25(14):7776. doi: 10.3390/ijms25147776.
The gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria-endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a flox allele in a pure C57BL/6N mouse background and the subsequent creation of knockout (KO) mice via Cre-recombination. Our KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.
该基因编码一种称为 VPS13A 的脂质转运蛋白，也称为 chorein，与线粒体相关内质网（ER）膜（MAMs）、线粒体-内体和脂滴有关。该蛋白在细胞器间通讯和脂质转运中发挥着关键作用。该基因的突变与舞蹈棘红细胞增多症（ChAc）的发病机制有关，ChAc 是一种罕见的常染色体隐性神经退行性疾病，其特征为舞蹈症、面口运动障碍、运动过度、癫痫、认知障碍和棘红细胞增多症。先前的 ChAc 小鼠模型显示出不同的疾病表型，这取决于遗传背景。在这项研究中，我们报告了在纯 C57BL/6N 小鼠背景下产生的 flox 等位基因，以及通过 Cre 重组产生的 敲除（KO）小鼠。我们的 KO 小鼠在外周血涂片上表现出网织红细胞增加，但没有棘红细胞。此外，在纹状体和中枢神经系统的基底神经节中，GFAP 和 Iba1 阳性细胞没有显著差异。有趣的是，我们观察到异常的精子发生导致男性不育。这些发现表明 KO 小鼠是研究男性不育和 ChAc 某些血液学方面的有价值的模型。
