The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra‐Bosch‐Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss‐of‐function mutations of the transcriptional regulator NR2F1 . Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria‐like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long‐term self‐renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6 . In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area‐specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.

中文翻译：

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NR2F1调节BBSOAS患者的小鼠新皮层中区域祖细胞动力学和皮质回旋。

迄今为止，尚未完全阐明受损的皮质发育与神经发育障碍中随之而来的畸形之间的关系，以及与这些过程有关的基因。在这项研究中，我们报告了六例受BBSOAS（Boonstra-Bosch-Schaff视神经萎缩综合征）影响的新病例，BBSOAS是一种新兴的罕见神经发育障碍，由转录调节因子NR2F1的功能丧失突变引起。NR2F1单倍剂量不足的年轻患者显示轻度至中度智力障碍，并在顶叶和枕叶皮层中显示出可重现的多小胶质细胞样脑畸形。使用最近建立的BBSOAS小鼠模型，我们发现Nr2f1通过调节细胞周期基因和关键的皮层发育主基因（例如Pax6）来调节神经祖细胞的长期自我更新。在人类胎儿皮层中，不同的NR2F1表达水平涵盖回旋和沟，并与局部神经源性活动相关。此外，大脑类器官中的NR2F1水平降低会影响神经发生和PAX6表达。我们建议将NR2F1用作小鼠和人脑形态的区域特异性调节剂以及异常回旋的新型致病基因。