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Abstract：
Although the identification of numerous genes involved in neurodevelopmental disorders (NDDs) has reshaped our understanding of their etiology, there are still major obstacles in the way of developing therapeutic solutions for intellectual disability (ID) and other NDDs. These include extensive clinical and genetic heterogeneity, rarity of recurrent pathogenic variants, and comorbidity with other psychiatric traits. Moreover, a large intragenic mutational landscape is at play in some NDDs, leading to a broad range of clinical symptoms. Such diversity of symptoms is due to the different effects DNA variations have on protein functions and their impacts on downstream biological processes. The type of functional alterations, such as loss or gain of function, and interference with signaling pathways, has yet to be correlated with clinical symptoms for most genes. This review aims at discussing our current understanding of how the molecular changes of group I p21-activated kinases (PAK1, 2 and 3), which are essential actors of brain development and function; contribute to a broad clinical spectrum of NDDs. Identifying differences in PAK structure, regulation and spatio-temporal expression may help understanding the specific functions of each group I PAK. Deciphering how each variation type affects these parameters will help uncover the mechanisms underlying mutation pathogenicity. This is a prerequisite for the development of personalized therapeutic approaches.
摘要：
尽管与神经发育障碍（NDD）有关的许多基因的鉴定重塑了我们对其病因的理解，在开发智力残疾(ID)和其他NDD的治疗方案方面仍然存在主要障碍.这些包括广泛的临床和遗传异质性，罕见的复发性致病变异，以及与其他精神病学特征的共病。此外，一个巨大的基因内突变景观在一些NDD中起作用，导致广泛的临床症状。这种症状的多样性是由于DNA变异对蛋白质功能的不同影响及其对下游生物过程的影响。功能改变的类型，例如功能的丧失或获得，以及对信号通路的干扰，尚未与大多数基因的临床症状相关。这篇综述旨在讨论我们目前对I组p21活化激酶（PAK1，2和3）的分子变化的理解，它们是大脑发育和功能的重要参与者；有助于广泛的NDD临床谱。识别PAK结构的差异，调控和时空表达可能有助于理解每组PAK的特定功能。解密每种变异类型如何影响这些参数将有助于揭示潜在的突变致病性机制。这是开发个性化治疗方法的先决条件。
