自閉癥（*）是一類常見的神經(jīng)發(fā)育疾病,，主要癥狀是患者患有嚴重的社交,、行為的功能障礙,。有研究認為遺傳組成使得一些個體容易患有自閉癥，而且還分析了一些與自閉癥相關(guān)的基因,。盡管人類的7號染色體被認為與自閉癥的易感性密切相關(guān)，但一直沒有研究者找到該區(qū)域里與自閉癥直接相關(guān)的基因?，F(xiàn)在，來自日本理化學研究所腦科學研究所（**）的研究者卻在該區(qū)域找到了這樣一個基因,，發(fā)現(xiàn)缺乏CADPS2蛋白的小鼠表現(xiàn)出類似自閉癥的癥狀。
研究文章刊登在3月22日的《the Journal of Clinical Investigation》雜志上,，Teiichi Furuichi和同事發(fā)現(xiàn)缺乏CADPS2（對應于人類7號染色體易感區(qū)上的一個基因）的小鼠,，在社會互動方面存在障礙：兩只素未謀面的CADPS2缺失的小鼠相互接觸的頻率,，要比兩只野生型小鼠明顯少得多,。同時,，這些CADPS2缺失的小鼠還伴有多動（***）癥狀和缺乏探索新環(huán)境的能力,，所有這些都是患有自閉癥個體的明顯特征。
還有一個非常重要的證據(jù),，患有自閉癥的患者在CADPS2 mRNA上存有異常,，而這在與他們親緣性非常高的健康的親戚身上卻未發(fā)現(xiàn),，更進一步地暗示CADPS2的功能異常很可能是自閉癥的一個誘因。
部分英文原文：
Published Online March 22, 2007
Online First Publication
Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients
Tetsushi Sadakata1, Miwa Washida1, Yoshimi Iwayama2, Satoshi Shoji1, Yumi Sato1, Takeshi Ohkura3, Ritsuko Katoh-Semba4, Mizuho Nakajima2, Yukiko Sekine1, Mika Tanaka5, Kazuhiko Nakamura6, Yasuhide Iwata6, Kenji J. Tsuchiya6, Norio Mori6, Sevilla D. Detera-Wadleigh7, Hironobu Ichikawa3, Shigeyoshi Itohara8, Takeo Yoshikawa2 and Teiichi Furuichi1
1Laboratory for Molecular Neurogenesis and 2Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Saitama, Japan. 3Tokyo Metropolitan Umegaoka Hospital, Tokyo, Japan. 4Department of Perinatology, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Japan. 5Research Resource Center, RIKEN Brain Science Institute, Saitama, Japan. 6Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan. 7Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, Maryland, USA. 8Laboratory for Behavioral Genetics, RIKEN Brain Science Institute, Saitama, Japan.
Address correspondence to: Teiichi Furuichi, Laboratory for Molecular Neurogenesis, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan. Phone: 81-48-467-6079; Fax: 81-48-467-6079; E-mail: [email protected] .
Received for publication May 9, 2006, and accepted in revised form January 16, 2007.
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 dense-core 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.
