Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders.
Species-conserved SYNGAP1 phenotypes associated with neurodevelopmental disorders.
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DOI：
10.1016/j.mcn.2018.03.008
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Rumbaugh G
中科院分区：
文献类型：
--
作者：
Kilinc M;Creson T;Rojas C;Aceti M;Ellegood J;Vaissiere T;Lerch JP;Rumbaugh G
SYNGAP 1功能丧失变体与智力残疾、严重癫痫、自闭症谱系障碍和精神分裂症有因果关系。虽然神经发育障碍（NDD）有数百种遗传风险因素，但该基因在某种程度上是独特的，因为在患者中发现的功能丧失变体的频率和频率与SYNGAP 1致病性相关的脑部疾病的范围相结合。这些临床发现表明，SYNGAP 1调节大脑发育所必需的基本神经发育过程。在这里，我们描述了四个表型域，控制跨脊椎动物物种的Syngap 1表达。两个领域，认知功能的成熟和兴奋抑制平衡的维持，完全通过对当前文献的回顾来定义。通过整合当前文献和新数据定义了两个额外的结构域，这些新数据表明SYNGAP 1/Syngap 1调节先天生存行为和大脑结构。这四个表型结构域通常在NDD中被破坏，这表明对发育Syngap 1功能的更深入理解将可推广到已知或未知病因的其他NDD。因此，我们讨论了已知的分子和细胞功能的Syngap 1，并考虑这些功能可能有助于疾病相关表型的出现。最后，我们确定了Syngap 1神经生物学的主要未开发领域，并讨论了如何更深入地了解这个基因可能会发现NDD病理生物学的一般原则。
SYNGAP1 loss-of-function variants are causally associated with intellectual disability, severe epilepsy, autism spectrum disorder and schizophrenia. While there are hundreds of genetic risk factors for neurodevelopmental disorders (NDDs), this gene is somewhat unique because of the frequency and penetrance of loss-of-function variants found in patients combined with the range of brain disorders associated with SYNGAP1 pathogenicity. These clinical findings indicate that SYNGAP1 regulates fundamental neurodevelopmental processes that are necessary for brain development. Here, we describe four phenotypic domains that are controlled by Syngap1 expression across vertebrate species. Two domains, the maturation of cognitive functions and maintenance of excitatory-inhibitory balance, are defined exclusively through a review of the current literature. Two additional domains are defined by integrating the current literature with new data indicating that SYNGAP1/Syngap1 regulates innate survival behaviors and brain structure. These four phenotypic domains are commonly disrupted in NDDs, suggesting that a deeper understanding of developmental Syngap1 functions will be generalizable to other NDDs of known or unknown etiology. Therefore, we discuss the known molecular and cellular functions of Syngap1 and consider how these functions may contribute to the emergence of disease-relevant phenotypes. Finally, we identify major unexplored areas of Syngap1 neurobiology and discuss how a deeper understanding of this gene may uncover general principles of NDD pathobiology.
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