Institute for Clinical Chemistry, University Hospital and University of Zürich, Zürich, Switzerland.
Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2023 Sep;1868(9):159359. doi: 10.1016/j.bbalip.2023.159359. Epub 2023 Jun 20.
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease. Recently, several gain-of-function mutations in SPTLC1 were associated with juvenile ALS. SPTLC1 encodes for a subunit of the serine-palmitoyltransferase (SPT) - the rate-limiting enzyme in the de novo synthesis of sphingolipids (SL). SPT activity, and thus SL de novo synthesis, is tightly controlled by a homeostatic feedback mechanism mediated by ORMDL proteins. Here we report a novel SPTLC1p.L38R mutation in a young Chinese girl with a signature of juvenile ALS. The patient presented with muscular weakness and atrophy, tongue tremor and fasciculation, breathing problems and positive pyramidal signs. All SPTLC1-ALS mutations including the SPTLC1 p.L38R are located within a single membrane-spanning domain of the protein and impede the interaction with the regulatory ORMDL subunit of SPT. Pertinent to the altered homeostatic control, lipid analysis showed overall increased SL levels in the patient plasma. An increased SPT activity and SL de novo synthesis was confirmed in p.L38R expressing HEK293 cells. Particularily dihydro-sphingolipids (dhSL) were signficantly increased in patient plasma and p.L38R mutant expressing cells. Increased dhSL formation has been previously linked to neurotoxicity and may be involved in the pathomechanism of SPTLC1-ALS mutations.
肌萎缩侧索硬化症（ALS）是一种进行性和致命的神经肌肉疾病。最近，SPTLC1 中的几个获得性功能突变与青少年 ALS 有关。SPTLC1 编码丝氨酸棕榈酰转移酶（SPT）的一个亚基 - 鞘脂（SL）从头合成的限速酶。SPT 活性，因此 SL 从头合成，受 ORMDL 蛋白介导的动态平衡反馈机制严格控制。在这里，我们报告了一个年轻的中国女孩中 SPTLC1p.L38R 突变的新发现，其特征是青少年 ALS。该患者表现为肌肉无力和萎缩、舌震颤和抽搐、呼吸问题和阳性锥体征。所有 SPTLC1-ALS 突变（包括 SPTLC1 p.L38R）都位于蛋白质的单个跨膜域内，并阻碍与 SPT 的调节 ORMDL 亚基的相互作用。与改变的动态平衡控制相关，脂质分析显示患者血浆中 SL 水平总体升高。在表达 p.L38R 的 HEK293 细胞中证实 SPT 活性和 SL 从头合成增加。患者血浆和表达 p.L38R 突变体的细胞中特别地二氢鞘脂（dhSL）显著增加。增加的 dhSL 形成以前与神经毒性有关，并且可能与 SPTLC1-ALS 突变的发病机制有关。
