Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients
Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients
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DOI：
10.1172/jci29031
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Furuichi, Teiichi
中科院分区：
文献类型：
--
作者：
Sadakata, Tetsushi;Washida, Miwa;Furuichi, Teiichi
自闭症是最常见的神经发育障碍，其特征是社会交往和沟通技能的严重障碍，其潜在的分子机制仍然未知。Ca 2+依赖性分泌激活蛋白2（CADPS 2;也称为CAPS 2）介导致密核囊泡的胞吐作用，并且人CADPS 2位于染色体7 q上的自闭症易感性基因座1内。在这里，我们表明，Cadps 2基因敲除小鼠不仅有受损的脑源性神经营养因子的释放，但也表现出自闭症样的细胞和行为表型。此外，我们发现了一个异常的选择性剪接CADPS 2 mRNA，缺乏外显子3在一些自闭症患者。外显子3编码dynactin 1结合域，影响轴突CADPS 2蛋白的分布。我们的研究结果表明，CADPS 2介导的神经营养因子释放的干扰有助于自闭症易感性。
Autism, characterized by profound impairment in social interactions and communicative skills, is the most common neurodevelopmental disorder, and its underlying molecular mechanisms remain unknown. Ca2+-dependent activator protein for secretion 2 (CADPS2; also known as CAPS2) mediates the exocytosis of densecore vesicles, and the human CADPS2 is located within the autism susceptibility locus 1 on chromosome 7q. Here we show that Cadps2-knockout mice not only have impaired brain-derived neurotrophic factor release but also show autistic-like cellular and behavioral phenotypes. Moreover, we found an aberrant alternatively spliced CADPS2 mRNA that lacks exon 3 in some autistic patients. Exon 3 was shown to encode the dynactin 1-binding domain and affect axonal CADPS2 protein distribution. Our results suggest that a disturbance in CADPS2-mediated neurotrophin release contributes to autism susceptibility.