The de novo ceramide synthesis pathway is essential to human biology and health, but genetic influences remain unexplored. The core function of this pathway is the generation of biologically active ceramide from its precursor, dihydroceramide. Dihydroceramides have diverse, often protective, biological roles; conversely, increased ceramide levels are biomarkers of complex disease. To explore the genetics of the ceramide synthesis pathway, we searched for deleterious nonsynonymous variants in the genomes of 1,020 Mexican Americans from extended pedigrees. We identified a Hispanic ancestry-specific rare functional variant, L175Q, in delta 4-desaturase, sphingolipid 1 (DEGS1), a key enzyme in the pathway that converts dihydroceramide to ceramide. This amino acid change was significantly associated with large increases in plasma dihydroceramides. Indexes of DEGS1 enzymatic activity were dramatically reduced in heterozygotes. CRISPR/Cas9 genome editing of HepG2 cells confirmed that the L175Q variant results in a partial loss of function for the DEGS1 enzyme. Understanding the biological role of DEGS1 variants, such as L175Q, in ceramide synthesis may improve the understanding of metabolic-related disorders and spur ongoing research of drug targets along this pathway.

中文翻译：

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罕见的 DEGS1 变异显着改变神经酰胺从头合成途径。


神经酰胺从头合成途径对于人类生物学和健康至关重要，但遗传影响仍未得到探索。该途径的核心功能是从其前体二氢神经酰胺生成具有生物活性的神经酰胺。二氢神经酰胺具有多种（通常是保护性）生物学作用；相反，神经酰胺水平升高是复杂疾病的生物标志物。为了探索神经酰胺合成途径的遗传学，我们在 1,020 名墨西哥裔美国人的基因组中寻找有害的非同义变异。我们在 delta 4-去饱和酶鞘脂 1 (DEGS1) 中发现了西班牙裔特有的罕见功能变异 L175Q，DEGS1 是二氢神经酰胺转化为神经酰胺途径中的关键酶。这种氨基酸的变化与血浆二氢神经酰胺的大量增加显着相关。杂合子中 DEGS1 酶活性指数显着降低。 HepG2 细胞的 CRISPR/Cas9 基因组编辑证实，L175Q 变异会导致 DEGS1 酶部分功能丧失。了解DEGS1变体（例如 L175Q）在神经酰胺合成中的生物学作用可能会增进对代谢相关疾病的理解，并促进沿着该途径的药物靶标的持续研究。