Sphingolipids (SL) represent a structurally diverse class of lipids that are central to cellular physiology and neuronal development and function. Defects in the sphingolipid metabolism are typically associated with nervous system disorders. The C4-dihydroceramide desaturase (DEGS1) catalyzes the conversion of dihydroceramide to ceramide, the final step in the SL de-novo synthesis. Loss of function mutations in DEGS1 cause a hypomyelinating leukodystrophy, which is associated with increased plasma dihydrosphingolipids (dhSL) and with the formation of an atypical SPB 18:1(14Z);O2 metabolite. Here, we characterize two novel DEGS1 variants of unknown significance (VUS), provide a structural model with a predicted substrate binding site and propose a regulatory link between DEGS1 and fatty acid desaturase 3 (FADS3). Both VUS involve single amino acid substitutions near the C-terminus within conserved regions of the enzyme. Patient 1 (p.R311K variant) shows severe progressive tetraspasticity, intellectual disability, and epilepsy in combination with brain magnetic resonance imaging (MRI) findings, typical for DEGS1-related leukodystrophy. Patient 2 (p.G270E variant) presents with delayed psychomotor development, oculomotor apraxia, and a normal brain MRI. Plasma from the p.R311K carrier showed a significantly elevated dhSL species and the presence of SPB 18:1(14Z);O2, while the plasma SL profile for the p.G270E variant was not altered. This suggests the p.R331K variant is pathogenic, while the p.G270E appears benign. As an increase in dihydroSL species is also seen in other pathological disorders of the SL metabolism, the SPB 18:1(14Z);O2 seems to be a more specific biomarker to discriminate between pathogenic and benign DEGS1 variants.

中文翻译：

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非典型鞘脂 SPB 18:1(14Z);O2 是 DEGS1 相关低髓鞘性脑白质营养不良的生物标志物。

鞘脂 (SL) 代表一类结构多样的脂质，对于细胞生理学以及神经元发育和功能至关重要。鞘脂代谢缺陷通常与神经系统疾病有关。C4-二氢神经酰胺去饱和酶 (DEGS1) 催化二氢神经酰胺转化为神经酰胺，这是 SL 从头合成的最后一步。DEGS1 功能缺失突变会导致髓鞘形成性脑白质营养不良，这与血浆二氢鞘脂 (dhSL) 增加以及非典型 SPB 18:1(14Z);O2 代谢物的形成有关。在这里，我们表征了两种意义不明的新 DEGS1 变体 (VUS)，提供了具有预测底物结合位点的结构模型，并提出了 DEGS1 和脂肪酸去饱和酶 3 (FADS3) 之间的调控联系。两种 VUS 都涉及酶保守区域内 C 末端附近的单个氨基酸取代。患者 1（p.R311K 变异）表现出严重的进行性四肢痉挛、智力障碍和癫痫，并伴有脑部磁共振成像 (MRI) 结果，这是典型的 DEGS1 相关脑白质营养不良。患者 2（p.G270E 变异）表现为精神运动发育迟缓、动眼神经失用和脑部 MRI 正常。来自 p.R311K 载体的血浆显示 dhSL 种类显着升高，并且存在 SPB 18:1(14Z);O2，而 p.G270E 变体的血浆 SL 谱没有改变。这表明 p.R331K 变体是致病性的，而 p.G270E 似乎是良性的。由于二氢 SL 种类的增加也见于 SL 代谢的其他病理性疾病中，因此 SPB 18:1(14Z);O2 似乎是区分致病性和良性 DEGS1 变异的更特异的生物标志物。