Lehr Alexander W, McDaniel Kathryn F, Roche Katherine W
Receptor Biology Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Department of Neuroscience, Brown University, Providence, RI 02906, USA.
Genes (Basel). 2024 Dec 14;15(12):1601. doi: 10.3390/genes15121601.
Neuroligins (NLGNs) are postsynaptic adhesion molecules critical for neuronal development that are highly associated with autism spectrum disorder (ASD). Here, we provide an overview of the literature on rare variants. In addition, we introduce a new approach to analyze human variation within genes to identify sensitive regions that have an increased frequency of ASD-associated variants to better understand NLGN function. : To identify critical protein subdomains within the gene family, we developed an algorithm that assesses tolerance to missense mutations in human genetic variation by comparing clinical variants from ClinVar to reference variants from gnomAD. This approach provides tolerance values to subdomains within the protein. : Our algorithm identified several critical regions that were conserved across multiple NLGN isoforms. Importantly, this approach also identified a previously reported cluster of pathogenic variants in (also conserved in and ) as well as a region around the highly characterized NLGN3 R451C ASD-associated mutation. Additionally, we highlighted other, as of yet, uncharacterized regions enriched with mutations. : The systematic analysis of NLGN ASD-associated variants compared to variants identified in the unaffected population (gnomAD) reveals conserved domains in NLGN isoforms that are tolerant to variation or are enriched in clinically relevant variants. Examination of databases also allows for predictions of the presumed tolerance to loss of an allele. The use of the algorithm we developed effectively allowed the evaluation of subdomains of NLGNs and can be used to examine other ASD-associated genes.
神经连接蛋白（NLGNs）是对神经元发育至关重要的突触后黏附分子，与自闭症谱系障碍（ASD）高度相关。在此，我们概述了关于罕见变异的文献。此外，我们引入了一种新方法来分析基因内的人类变异，以识别与ASD相关变异频率增加的敏感区域，从而更好地理解NLGN的功能。：为了识别该基因家族内的关键蛋白质亚结构域，我们开发了一种算法，通过将ClinVar中的临床变异与gnomAD中的参考变异进行比较，评估人类遗传变异中错义突变的耐受性。这种方法为蛋白质内的亚结构域提供了耐受性值。：我们的算法识别出了多个NLGN异构体中保守的几个关键区域。重要的是，这种方法还识别出了先前报道的（在和中也保守）的致病变异簇以及高度特征化的NLGN3 R451C ASD相关突变周围的一个区域。此外，我们突出了其他尚未表征的富含突变的区域。：与在未受影响人群（gnomAD）中鉴定出的变异相比，对与NLGN ASD相关变异的系统分析揭示了NLGN异构体中对变异具有耐受性或富含临床相关变异的保守结构域。对数据库的检查还允许预测等位基因缺失的假定耐受性。我们开发的算法的使用有效地允许对NLGNs的亚结构域进行评估，并可用于检查其他与ASD相关的基因。
