Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.

中文翻译：

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YIF1B 突变导致与高尔基体和初级纤毛改变相关的产后神经发育综合征

人类出生后神经发育迟缓通常与大脑改变有关，这些改变可单独或与外周缺陷有关，导致过早死亡。在这里，我们报告了来自六个独立家族的 10 名患者的临床特征，这些患者的常染色体YIF1B基因编码普遍存在的蛋白质，该蛋白质参与从内质网到细胞膜的顺行运输，以及高尔基体形态。患者表现出全面发育迟缓、运动迟缓、视觉缺陷以及脑室扩大、髓鞘改变和小脑萎缩的脑部 MRI 证据。在Yif1b中观察到类似的配置文件开发敲除 (KO) 小鼠模型以识别与临床缺陷相关的细胞改变。在中枢神经系统中，缺乏Yif1b 的小鼠表现出神经元减少、运动皮层髓鞘形成改变、小脑萎缩、心室扩大以及内质网和高尔基体隔室的亚细胞改变。值得注意的是，虽然在初级纤毛中未检测到 YIF1B，但双等位基因YIF1B突变导致患者和Yif1b -KO 小鼠皮肤成纤维细胞中的初级纤毛异常，以及Yif1b -KO 大脑中的纤毛结构成分。因此，我们的发现确定了YIF1B作为人类出生后早期发育的必需基因，并提供了一个新的遗传目标，应该在生命第一年出现神经发育延迟的患者中进行测试。因此，我们的工作首次描述了连接高尔基病和纤毛病的功能缺陷，这些疾病迄今为止仅与编码初级纤毛或相关超微结构中表达的蛋白质的基因突变相关。因此，我们建议应将这些病理视为属于更大类别的神经发育疾病，这取决于参与蛋白质向特定细胞膜隔室运输的蛋白质。