Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.
Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.
复制标题
DOI：
10.1093/brain/awac106
复制
发表时间：
2022-09-14
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
RAC3的变异编码一个小的GTPase RAC3，它对肌动蛋白细胞骨架和细胞内信号转导的调节至关重要，与一种罕见的神经发育障碍有关，包括结构性脑异常和面部畸形。我们调查了一组10名不相关的参与者，他们表现为整体精神运动迟缓、张力低下、行为障碍、刻板运动、畸形特征、癫痫发作和肌肉骨骼异常。脑MRI显示多种脑畸形，包括胼胝体异常、白质变薄、灰质异位、多小脑回/脑回异常、脑干异常和小脑发育不良。这些患者携带8种不同的新生RAC3变体，包括6种新变体（NM_005052.3）： C . 34g > C p.G12R, C . 179g > A p.G60D, C . 186_188delgga p.E62del, C . 187g > A p.D63N, C . 191a > G p.Y64C和C . 348g > C p.K116N。然后，我们检测了这些新的和先前报道的致病变异p.P29L、p.P34R、p.p a59g、p.p q61l和p.p e62k的病理生理意义。体外分析显示，所有测试的RAC3变体都具有不同程度的生化和生物活性，并且对下游效应物（包括p21活化的激酶1）具有不同的亲和力。然后，我们重点研究了Switch II区域的四个变体p.Q61L, p.E62del, p.D63N和p.Y64C，该区域对小gtpase的生化活性至关重要，也是Rho家族其他基因RAC1和CDC42共同的变异热点。在胚胎小鼠大脑中使用子宫电穿孔急性表达这四种变体导致皮质神经元形态和迁移缺陷，最终在皮质发生过程中形成簇状。值得注意的是，p.E62del、p.D63N和p.Y64C的迁移缺陷被p21活化激酶1的显性阴性版本所挽救。我们的研究结果表明，在大脑发育过程中，RAC3变异通过变异特异性机制导致皮质神经元的形态和功能缺陷，最终导致异质的神经发育表型。Scala等人在10个具有神经发育表型的不相关受试者中发现了6个编码小GTPase的RAC3从头变异体。小鼠体内和体外分析表明，RAC3变异通过变异特异性机制导致皮质神经元的形态功能缺陷，破坏皮质发生。
Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes. Scala et al. identify six de novo variants in RAC3, which encodes a small GTPase, in 10 unrelated subjects with neurodevelopmental phenotypes. In vivo and in vitro analyses in mice reveal that RAC3 variants cause morpho-functional defects in cortical neurons through variant-specific mechanisms, disrupting corticogenesis.
登录
查看更多内容
影响因子：
7.8
作者：
Albertinazzi, C;Gilardelli, D;de Curtis, I
通讯作者：
de Curtis, I
影响因子：
2.9
作者：
Amano, Mutsuki;Nakayama, Masanori;Kaibuchi, Kozo
通讯作者：
Kaibuchi, Kozo
影响因子：
4.8
作者：
Haataja, L;Groffen, J;Heisterkamp, N
通讯作者：
Heisterkamp, N
影响因子：
4.8
作者：
Corbetta, Sara;Gualdoni, Sara;de Curtis, Ivan
通讯作者：
de Curtis, Ivan
影响因子：
--
作者：
Alan, Jamie K;Lundquist, Erik A
通讯作者：
Lundquist, Erik A