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.

中文翻译：

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PNPLA8 中的双等位基因无效变异通过减少基底放射状胶质细胞的数量而引起小头畸形


含有 Patatin 样磷脂酶结构域的脂肪酶 8 （PNPLA8） 是钙非依赖性磷脂酶 A2 酶之一，通过维持膜磷脂参与各种生理过程。PNPLA8 中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，对表型谱、基因型-表型相关性和潜在机制知之甚少。在这里，我们新发现了来自 12 个不相关家系的 14 个个体，这些个体在 PNPLA8 中具有双等位基因超罕见变异，表现出广泛的临床特征表型谱。对当前和先前报告的个体 （20 个家庭的 25 名受影响个体） 的临床特征的分析表明，PNPLA8 相关神经系统疾病表现为从可变发育和/或退行性癫痫运动障碍脑病到儿童期发作的神经变性的连续体。我们发现 PNPLA8 的完全缺失与更深的一端有关，即先天性小头畸形。使用由人类诱导多能干细胞产生的脑类器官，我们发现 PNPLA8 的缺失通过减少基底放射状神经胶质细胞和上层神经元的数量导致发育缺陷。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特征，这反映在与细胞周期、基底放射状神经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神经胶质细胞数量的减少部分是通过添加溶血磷脂酸来挽救的。我们的数据表明，PNPLA8 对于满足磷脂合成需求和在人脑发育中产生丰富的基底放射状神经胶质细胞至关重要。