Deficiency of the endoplasmic reticulum transmembrane protein ARV1 leads to epileptic encephalopathy in humans and in mice. ARV1 is highly conserved, but its function in human cells is unknown. Studies of yeast arv1 null mutants indicate that it is involved in a number of biochemical processes including the synthesis of sphingolipids and glycosylphosphatidylinositol (GPI), a glycolipid anchor that is attached to the C-termini of many membrane bound proteins. GPI anchors are post-translational modifications, enabling proteins to travel from the endoplasmic reticulum (ER) through the Golgi and to attach to plasma membranes. We identified a homozygous pathogenic mutation in ARV1, p.Gly189Arg, in two brothers with infantile encephalopathy, and characterized the biochemical defect caused by this mutation. In addition to reduced expression of ARV1 transcript and protein in patients’ fibroblasts, complementation tests in yeast showed that the ARV1 p.Gly189Arg mutation leads to deficient maturation of Gas1, a GPI-anchored protein, but does not affect sphingolipid synthesis. Our results suggest, that similar to mutations in other proteins in the GPI-anchoring pathway, including PIGM, PIGA, and PIGQ, ARV1 p.Gly189Arg causes a GPI anchoring defect and leads to early onset epileptic encephalopathy.

中文翻译：

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GPI合成中的缺陷是ARV1在智障和癫痫发作中的作用机制。

内质网跨膜蛋白ARV1的缺乏会导致人类和小鼠的癫痫性脑病。ARV1是高度保守的，但在人类细胞中的功能尚不清楚。酵母arv1 null突变体的研究表明，它参与许多生化过程，包括鞘脂和糖基磷脂酰肌醇（GPI）的合成，糖脂锚定蛋白附着于许多膜结合蛋白的C-末端。GPI锚是翻译后修饰，使蛋白质能够从内质网（ER）穿过高尔基体，并附着在质膜上。我们确定了ARV1的纯合致病性突变p.Gly189Arg，在两个患有婴儿脑病的兄弟中，并描述了由该突变引起的生化缺陷。除了减少患者成纤维细胞中ARV1转录物和蛋白质的表达外，酵母中的互补试验还表明，ARV1 p.Gly189Arg突变导致GPI固定蛋白Gas1的成熟不足，但不影响鞘脂的合成。我们的结果表明，类似于GPI锚定途径中其他蛋白的突变，包括PIGM，PIGA和PIGQ，ARV1 p.Gly189Arg会引起GPI锚定缺陷并导致早期发作的癫痫性脑病。