Pant Devesh C, Lone Museer A, Parameswaran Janani, Ma Fuying, Dutta Prisha, Wang Zitong, Park Jaekeun, Verma Sumit, Hornemann Thorsten, Jiang Jie
Department of Cell Biology, Emory University, Atlanta, GA, USA.
Institute for Clinical Chemistry, University of Zurich, Zurich, Switzerland.
bioRxiv. 2025 Feb 23:2025.02.18.638951. doi: 10.1101/2025.02.18.638951.
Mutations in the human gene have recently been linked to early onset amyotrophic lateral sclerosis (ALS), characterized by global atrophy, motor impairments, and symptoms such as tongue fasciculations. All known ALS-linked mutations cluster within exon 2 and a specific variant, c.58G>T, results in exon 2 skipping. However, it is unclear how the exon 2 deletion affects SPTLC1 function and contributes to ALS pathogenesis. Leveraging the high genomic sequence similarity between mouse and human , we created a novel mouse model with a CRISPR/Cas9-mediated deletion of exon 2 in the endogenous murine locus. While heterozygous mice did not develop motor defects or ALS-like neuropathology, homozygous mutants died prematurely. These findings indicate that ΔExon2 heterozygous mice do not replicate the disease phenotype but provide valuable insights into SPTLC1 biology and serve as a useful resource for future mechanistic studies.
人类基因的突变最近被认为与早发性肌萎缩侧索硬化症（ALS）有关，其特征为全身性萎缩、运动障碍以及如舌肌束颤等症状。所有已知的与ALS相关的突变都集中在外显子2内，一种特定的变体c.58G>T会导致外显子2跳跃。然而，尚不清楚外显子2缺失如何影响SPTLC1功能并促成ALS发病机制。利用小鼠和人类之间高度的基因组序列相似性，我们创建了一种新型小鼠模型，通过CRISPR/Cas9介导删除内源性小鼠基因座中的外显子2。虽然杂合小鼠未出现运动缺陷或ALS样神经病理学变化，但纯合突变体过早死亡。这些发现表明，ΔExon2杂合小鼠并未复制疾病表型，但为SPTLC1生物学提供了有价值的见解，并为未来的机制研究提供了有用的资源。
