Molecular Medicine, IRCCS Stella Maris Foundation, Viale del Tirreno 331, via dei Giacinti 2, 56128, Calambrone, Pisa, Italy.
Clinical Neurophysiology Laboratory, IRCCS Stella Maris Foundation, Viale del Tirreno 331, via dei Giacinti 2, 56128, Calambrone, Pisa, Italy.
Neuromolecular Med. 2016 Mar;18(1):69-80. doi: 10.1007/s12017-015-8378-2. Epub 2015 Nov 4.
The frequent co-occurrence of autism spectrum disorders (ASD) and epilepsy, or paroxysmal EEG abnormalities, defines a condition termed autism-epilepsy phenotype (AEP). This condition results, in some cases , from dysfunctions of glial inwardly rectifying potassium channels (Kir), which are mainly expressed in astrocytes where they mediate neuron-glia communication. Macrocephaly is also often comorbid with autism-epilepsy (autism-epilepsy phenotype with macrocephaly, MAEP), and it is tempting to hypothesize that shared pathogenic mechanisms might explain concurrence of these conditions. In the present study, we assessed whether protein pathways involved, along with Kir channels, in astrocyte-neuron interaction at the tripartite synapse play a role in the etiopathogenesis of MAEP. Using a targeted resequencing methodology, we investigated the coding regions of 35 genes in 61 patients and correlated genetic results with clinical features. Variants were subdivided into 12 classes and clustered into four groups. We detected rare or previously unknown predicted deleterious missense changes in GJA1, SLC12A2, SNTA1, EFNA3, CNTNAP2, EPHA4, and STXBP1 in seven patients and two high-frequency variants in DLG1 in six individuals. We also found that a group of variants (predicted deleterious and non-coding), segregating with the comorbid MAEP/AEP subgroups, belong to proteins specifically involved in glutamate transport and metabolism (namely, SLC17A6, GRM8, and GLUL), as well as in potassium conductance (KCNN3). This "endophenotype-oriented" study, performed using a targeted strategy, helped to further delineate part of the complex genetic background of ASD, particularly in the presence of coexisting macrocephaly and/or epilepsy/paroxysmal EEG, and suggests that use of stringent clinical clustering might be an approach worth adopting in order to unravel the complex genomic data in neurodevelopmental disorders.
自闭症谱系障碍（ASD）和癫痫，或阵发性脑电图异常频繁同时出现，定义了一种称为自闭症-癫痫表型（AEP）的病症。在某些情况下，这种病症是由于内向整流钾通道（Kir）的神经胶质功能障碍引起的，Kir 主要在星形胶质细胞中表达，在那里它们介导神经元-胶质细胞通讯。大头畸形也常与自闭症-癫痫（自闭症-癫痫表型伴大头畸形，MAEP）共病，人们不禁假设共同的致病机制可能解释这些病症的同时发生。在本研究中，我们评估了在三突触星形胶质细胞-神经元相互作用中与 Kir 通道一起参与的蛋白途径是否在 MAEP 的发病机制中起作用。使用靶向重测序方法，我们研究了 61 名患者的 35 个基因的编码区，并将遗传结果与临床特征相关联。变体被分为 12 类，并聚类为 4 组。我们在 7 名患者和 2 名患者中检测到 GJA1、SLC12A2、SNTA1、EFNA3、CNTNAP2、EPHA4 和 STXBP1 中罕见或以前未知的预测有害错义变化，以及 6 名个体中 DLG1 中的两个高频变体。我们还发现，一组变体（预测有害和非编码）与共病 MAEP/AEP 亚组一起分离，属于专门参与谷氨酸转运和代谢的蛋白（即 SLC17A6、GRM8 和 GLUL），以及钾电导（KCNN3）。这项使用靶向策略进行的“表型定向”研究有助于进一步描绘 ASD 复杂遗传背景的一部分，特别是在存在共存的大头畸形和/或癫痫/阵发性 EEG 的情况下，并表明使用严格的临床聚类可能是一种值得采用的方法，以便阐明神经发育障碍的复杂基因组数据。
