Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described. We identified three patients with heterozygous MPP5 de novo variants (DNV) and global developmental delay (GDD) and compared their phenotypes and magnetic resonance imaging (MRI) to ascertain how MPP5 DNV leads to GDD. All three patients with MPP5 DNV experienced GDD with language delay/regression and behavioral changes. MRI ranged from normal to decreased gyral folding and microcephaly. The effects of MPP5 depletion on the developing brain were assessed by creating a heterozygous conditional knock out (het CKO) murine model with central nervous system (CNS)-specific Nestin-Cre drivers. In the het CKO model, Mpp5 depletion led to microcephaly, decreased cerebellar volume and cortical thickness. Het CKO mice had decreased ependymal cells and Mpp5 at the apical surface of cortical ventricular zone compared with wild type. Het CKO mice also failed to maintain progenitor pools essential for neurogenesis. The proportion of cortical cells undergoing apoptotic cell death increased, suggesting that cell death reduces progenitor population and neuron number. Het CKO mice also showed behavioral changes, similar to our patients. To our knowledge, this is the first report to show that variants in MPP5 are associated with GDD, behavioral abnormalities and language regression/delay. Murine modeling shows that neurogenesis is likely altered in these individuals, with cell death and skewed cellular composition playing significant roles.

中文翻译：

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MPP5 中的从头变异导致全球发育迟缓和行为改变

膜蛋白棕榈酰化 5 (MPP5) 是一种高度保守的顶端复合蛋白，对细胞极性、命运和存活至关重要。细胞极性缺陷与神经系统疾病有关，包括自闭症和小头畸形。MPP5对于动物模型中的神经发生至关重要，但尚未描述导致神经功能障碍的人类变异。我们确定了三名患有杂合MPP5 从头变异 (DNV) 和全球发育迟缓 (GDD) 的患者，并比较了他们的表型和磁共振成像 (MRI)，以确定MPP5 DNV如何导致 GDD。所有三名MPP5患者DNV 经历了语言延迟/回归和行为改变的 GDD。MRI 范围从正常到减少的回旋折叠和小头畸形。通过创建具有中枢神经系统 (CNS) 特异性 Nestin-Cre 驱动程序的杂合条件敲除 (het CKO) 小鼠模型，评估 MPP5 耗竭对发育中大脑的影响。在 het CKO 模型中，Mpp5 耗竭导致小头畸形、小脑体积和皮质厚度减少。与野生型相比，Het CKO 小鼠皮质脑室区顶端表面的室管膜细胞和 Mpp5 减少。Het CKO 小鼠也未能维持对神经发生至关重要的祖细胞池。经历凋亡细胞死亡的皮质细胞比例增加，表明细胞死亡减少了祖细胞数量和神经元数量。Het CKO 小鼠也表现出与我们的患者相似的行为变化。据我们所知，这是第一份报告显示MPP5与 GDD、行为异常和语言退化/延迟相关。小鼠模型表明，这些个体的神经发生可能发生了改变，细胞死亡和细胞组成的扭曲起着重要作用。