Phosphoinositides are lipids that play a critical role in processes such as cellular signalling, ion channel activity and membrane trafficking. When mutated, several genes that encode proteins that participate in the metabolism of these lipids give rise to neurological or developmental phenotypes. PI4KA is a phosphoinositide kinase that is highly expressed in the brain and is essential for life. Here we used whole exome or genome sequencing to identify 10 unrelated patients harbouring biallelic variants in PI4KA that caused a spectrum of conditions ranging from severe global neurodevelopmental delay with hypomyelination and developmental brain abnormalities to pure spastic paraplegia. Some patients presented immunological deficits or genito-urinary abnormalities. Functional analyses by western blotting and immunofluorescence showed decreased PI4KA levels in the patients’ fibroblasts. Immunofluorescence and targeted lipidomics indicated that PI4KA activity was diminished in fibroblasts and peripheral blood mononuclear cells. In conclusion, we report a novel severe metabolic disorder caused by PI4KA malfunction, highlighting the importance of phosphoinositide signalling in human brain development and the myelin sheath.

中文翻译：

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双等位基因 PI4KA 变体导致一种新的神经发育综合征伴髓鞘性脑白质营养不良

磷酸肌醇是在细胞信号传导、离子通道活性和膜运输等过程中发挥关键作用的脂质。当发生突变时，编码参与这些脂质代谢的蛋白质的几个基因会产生神经或发育表型。PI4KA 是一种磷酸肌醇激酶，在大脑中高度表达，对生命至关重要。在这里，我们使用全外显子组或基因组测序来确定 10 名在 PI4KA 中携带双等位基因变异的无关患者，这些患者会导致一系列疾病，从严重的全球神经发育迟缓伴髓鞘形成和发育性大脑异常到单纯的痉挛性截瘫。一些患者表现出免疫缺陷或泌尿生殖系统异常。通过蛋白质印迹和免疫荧光进行的功能分析显示患者的成纤维细胞中 PI4KA 水平降低。免疫荧光和靶向脂质组学表明 PI4KA 活性在成纤维细胞和外周血单个核细胞中降低。总之，我们报告了一种由 PI4KA 故障引起的新型严重代谢紊乱，强调了磷酸肌醇信号在人脑发育和髓鞘中的重要性。