含 Patatin 样磷脂酶结构域的脂肪酶 8 (PNPLA8) 是一种不依赖于钙的磷脂酶 A2 酶，通过维持膜磷脂参与各种生理过程。 PNPLA8 的双等位基因变异与一系列儿科神经退行性疾病有关。然而，人们对表型谱、基因型-表型相关性和潜在机制知之甚少。在这里，我们新鉴定出来自 12 个不相关家族的 14 名个体，其 PNPLA8 具有双等位基因超罕见变异，呈现出广泛的临床特征表型谱。对当前和以前报道的个体（20个家庭的25个受影响个体）的临床特征的分析表明，PNPLA8相关的神经系统疾病表现为从可变的发育性和/或退行性癫痫运动障碍性脑病到儿童期发病的神经变性的连续体。我们发现 PNPLA8 的完全缺失与更严重的先天性小头畸形有关。利用人类诱导多能干细胞产生的大脑类器官，我们发现PNPLA8的缺失会减少基底放射状胶质细胞和上层神经元的数量，从而导致发育缺陷。空间转录组学显示，PNPLA8 的缺失改变了顶端放射状胶质细胞的命运规范，这反映在与细胞周期、基底放射状胶质细胞和神经分化相关的基因集的富集上。缺乏PNPLA8的神经祖细胞显示溶血磷脂酸、溶血磷脂酰乙醇胺和磷脂酸的量减少。患者来源的脑类器官中基底放射状胶质细胞数量的减少在一定程度上是通过添加溶血磷脂酸得到挽救的。我们的数据表明，PNPLA8 对于满足磷脂合成需求和在人类大脑发育中产生丰富的基底放射状胶质细胞至关重要。© 作者 2024。由牛津大学出版社代表大脑担保人出版。

Patatin-like phospholipase domain-containing lipase 8 (PNPLA8), one of the calcium-independent phospholipase A2 enzymes, is involved in various physiological processes through the maintenance of membrane phospholipids. Biallelic variants in PNPLA8 have been associated with a range of paediatric neurodegenerative disorders. However, the phenotypic spectrum, genotype-phenotype correlations and the underlying mechanisms are poorly understood. Here, we newly identified 14 individuals from 12 unrelated families with biallelic ultra-rare variants in PNPLA8 presenting with a wide phenotypic spectrum of clinical features. Analysis of the clinical features of current and previously reported individuals (25 affected individuals across 20 families) showed that PNPLA8-related neurological diseases manifest as a continuum ranging from variable developmental and/or degenerative epileptic-dyskinetic encephalopathy to childhood-onset neurodegeneration. We found that complete loss of PNPLA8 was associated with the more profound end of the spectrum, with congenital microcephaly. Using cerebral organoids generated from human induced pluripotent stem cells, we found that loss of PNPLA8 led to developmental defects by reducing the number of basal radial glial cells and upper-layer neurons. Spatial transcriptomics revealed that loss of PNPLA8 altered the fate specification of apical radial glial cells, as reflected by the enrichment of gene sets related to the cell cycle, basal radial glial cells and neural differentiation. Neural progenitor cells lacking PNPLA8 showed a reduced amount of lysophosphatidic acid, lysophosphatidylethanolamine and phosphatidic acid. The reduced number of basal radial glial cells in patient-derived cerebral organoids was rescued, in part, by the addition of lysophosphatidic acid. Our data suggest that PNPLA8 is crucial to meet phospholipid synthetic needs and to produce abundant basal radial glial cells in human brain development.© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.