Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium.
Hum Mol Genet. 2010 Apr 1;19(7):1368-78. doi: 10.1093/hmg/ddq013. Epub 2010 Jan 12.
Autism is a neurodevelopmental disorder characterized by impaired social reciprocity, impaired communication and stereotypical behaviors. Despite strong evidence for a genetic basis, few susceptibility genes have been identified. Here, we describe the positional cloning of SCAMP5, CLIC4 and PPCDC as candidate genes for autism, starting from a person with idiopathic, sporadic autism carrying a de novo chromosomal translocation. One of these genes, SCAMP5 is silenced on the derivative chromosome, and encodes a brain-enriched protein involved in membrane trafficking, similar to the previously identified candidate genes NBEA and AMISYN. Gene silencing of Nbea, Amisyn and Scamp5 in mouse beta-TC3 cells resulted in a 2-fold increase in stimulated secretion of large dense-core vesicles (LDCVs), while overexpression suppressed secretion. Moreover, ultrastructural analysis of blood platelets from the patients with haploinsufficieny of one of the three candidate genes, showed morphological abnormalities of dense-core granules, which closely resemble LDCVs. Taken together, this study shows that in three independent patients with autism three different negative regulators of LDCV secretion are affected, respectively, suggesting that in at least a subgroup of patients the regulation of neuronal vesicle trafficking may be involved in the pathogenesis of autism.
自闭症是一种神经发育障碍，其特征为社交互动受损、沟通障碍和刻板行为。尽管有强烈的遗传基础证据，但只发现了少数易感基因。在这里，我们描述了从一个患有特发性、散发性自闭症并携带新生染色体易位的患者开始，对 SCAMP5、CLIC4 和 PPCDC 作为自闭症候选基因进行定位克隆。这些基因中的一个，SCAMP5，在衍生染色体上被沉默，它编码一种在膜运输中丰富的脑蛋白，类似于先前鉴定的候选基因 NBEA 和 AMISYN。在小鼠β-TC3 细胞中沉默 Nbea、Amisyn 和 Scamp5 会导致受刺激的大致密核心囊泡（LDCV）分泌增加 2 倍，而过表达则抑制分泌。此外，对来自具有三个候选基因之一的杂合不足的患者的血小板的超微结构分析表明，致密核心颗粒存在形态异常，与 LDCV 非常相似。总之，这项研究表明，在三个患有自闭症的独立患者中，三个不同的 LDCV 分泌负调节剂分别受到影响，这表明在至少一个亚组患者中，神经元囊泡运输的调节可能与自闭症的发病机制有关。
