Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

中文翻译：

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顶端神经祖细胞对称细胞分裂的丧失导致 DENND5A 相关的发育性和癫痫性脑病

发育性癫痫性脑病 (DEE) 是一组异质性癫痫，其中大脑发育改变导致发育迟缓和癫痫发作，而癫痫活动进一步对神经发育产生负面影响。确定 DEE 的根本原因对于精准治疗的进展至关重要。在这里，我们描述了一组在 DENND5A 中具有双等位基因变异的个体，并确定变异类型与疾病严重程度相关。我们证明 DENND5A 与 MUPP1 和 PALS1 相互作用，MUPP1 和 PALS1 是 Crumbs 顶端极性复合物的组成部分，这对于神经祖细胞的身份和这些干细胞对称分裂的能力是必需的。缺乏DENND5A的诱导多能干细胞在神经诱导过程中无法进行对称细胞分裂，并且具有分化为神经元的固有倾向，而具有与人类综合征相似的表型的转基因DENND5A小鼠，其成年脑室下区的神经元数量增加。 DENND5A 缺失后对称细胞分裂的破坏是由于顶端神经祖细胞中有丝分裂纺锤体的错位造成的。 DENND5A 的一个子集定位于中心体，其定义有丝分裂期间的纺锤体极。缺乏 DENND5A 的细胞会远离心室周围的增殖性顶端区域，使子细胞偏向更加命运相关的状态，并最终缩短神经发生的周期。这项研究提供了 DENND5A 相关 DEE 背后的机制，可推广到其他发育状况，并为医生和家庭提供变异特异性临床信息。