Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects motor neurons. Mutations in the SPTLC1 subunit of serine palmitoyltransferase (SPT), which catalyzes the first step in the de novo synthesis of sphingolipids (SLs), cause childhood-onset ALS. SPTLC1-ALS variants map to a transmembrane domain that interacts with ORMDL proteins, negative regulators of SPT activity. We show that ORMDL binding to the holoenzyme complex is impaired in cells expressing pathogenic SPTLC1-ALS alleles, resulting in increased SL synthesis and a distinct lipid signature. C-terminal SPTLC1 variants cause peripheral hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to the synthesis of 1-deoxysphingolipids (1-deoxySLs) that form when SPT metabolizes L-alanine instead of L-serine. Limiting L-serine availability in SPTLC1-ALS–expressing cells increased 1-deoxySL and shifted the SL profile from an ALS to an HSAN1-like signature. This effect was corroborated in an SPTLC1-ALS pedigree in which the index patient uniquely presented with an HSAN1 phenotype, increased 1-deoxySL levels, and an L-serine deficiency. These data demonstrate how pathogenic variants in different domains of SPTLC1 give rise to distinct clinical presentations that are nonetheless modifiable by substrate availability.

中文翻译：

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与 ALS 相关的 SPTLC1 变体通过与 ORMDL 蛋白的相互作用受损产生不同的鞘脂特征

肌萎缩侧索硬化症 (ALS) 是一种影响运动神经元的进行性神经退行性疾病。SPTLC1中的突变丝氨酸棕榈酰转移酶 (SPT) 的亚基催化鞘脂 (SL) 从头合成的第一步，导致儿童期发作的肌萎缩侧索硬化。SPTLC1-ALS 变体映射到与 ORMDL 蛋白相互作用的跨膜结构域，ORMDL 蛋白是 SPT 活性的负调节因子。我们表明 ORMDL 与全酶复合物的结合在表达致病性 SPTLC1-ALS 等位基因的细胞中受损，导致 SL 合成增加和明显的脂质特征。由于 SPT 代谢 L-丙氨酸而不是 L-丝氨酸时形成的 1-脱氧鞘脂 (1-deoxySLs) 的合成，C 末端 SPTLC1 变体导致外周遗传性感觉和自主神经病 1 型 (HSAN1)。限制 L-丝氨酸在 SPTLC1-ALS 表达细胞中的可用性会增加 1-脱氧 SL，并将 SL 特征从 ALS 转变为 HSAN1 样特征。这种效应在 SPTLC1-ALS 谱系中得到证实，其中指示患者具有独特的 HSAN1 表型、1-脱氧 SL 水平升高和 L-丝氨酸缺乏症。这些数据证明了 SPTLC1 不同结构域中的致病变异如何导致不同的临床表现，这些表现仍然可以通过底物可用性进行修改。