Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.

中文翻译：

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RALGAPA1中的双等位基因变异会导致严重的神经发育障碍，肌肉性低钾症，婴儿痉挛和进食异常。

Ral（类Ras）GTPases在控制细胞迁移中起着重要作用，并与Ras介导的致瘤性有关。最近，还描述了RALA中的变异是导致智力残疾和发育迟缓的原因，这表明该途径与神经性儿科疾病有关。在这里，我们报告了RALGAPA1（编码Ral GTPase活化蛋白催化性α亚基1）中的双等位基因变异的鉴定，这些个体在四个无关的个体中具有深远的神经发育障碍，肌肉张力低下，进食异常，反复发烧和婴儿痉挛。call体发育异常伴有后部的局部变薄和特征性的面部特征似乎是统一的发现。来自两个受影响个体的成纤维细胞中不存在RalGAPA1，表明RALGAPA1变体的功能丧失。因此，在这些细胞系中增加了RalA活性，这与RalGAPA1缺乏引起RalA的组成性激活的想法相一致。此外，RalGAP复合物的脚手架亚基RalGAPB的水平显着降低，表明RalGAP复合物功能异常。此外，RalGAPA1缺乏明显增加了成纤维细胞中脂筏成分的细胞表面水平，这可能表明细胞生长信号的锚定依赖性受到干扰。我们的发现表明，RalA通路的失调对神经元功能和大脑发育具有重要影响。