Danish Epilepsy Center, Dianalund, Denmark.
Epilepsia. 2013 Feb;54(2):256-64. doi: 10.1111/epi.12078. Epub 2013 Jan 7.
Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs).
We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays.
We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE.
We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.
神经连接蛋白（Neurexins）是位于突触前终端的神经元粘附分子，其与突触后神经连接蛋白（Neuroligins）相互作用，形成一个跨突触复合物，是大脑中神经递质高效传递所必需的。最近，神经连接蛋白 1（NRXN1）基因的缺失和点突变与广泛的神经精神疾病有关。本研究旨在探讨 NRXN1 缺失是否也会增加特发性全面性癫痫（IGE）的风险。
我们使用高密度寡核苷酸微阵列对 1569 名 IGE 患者和 6201 名对照者的 NRXN1 基因缺失情况进行了筛选。
我们在 1569 名 IGE 患者中有 5 名和 6201 名对照者中有 2 名（p = 0.0049；比值比（OR）9.91，95%置信区间（CI）1.92-51.12）发现了 NRXN1 外显子缺失。在 IGE 家族中观察到复杂的家族遗传模式，表明杂合性 NRXN1 缺失是易感变异。有趣的是，我们在 5 名索引患者中的 3 名中鉴定出第二个大拷贝数变异，支持异质性易感等位基因在 IGE 病因中的作用。
我们的结论是，NRXN1 的外显子缺失是常见 IGE 综合征遗传复杂易感性的遗传风险因素。
