Tetsushi Sadakata, Miwa Washida, Yoshimi Iwayama, Satoshi Shoji, Yumi Sato, Takeshi Ohkura, Ritsuko Katoh-Semba, Mizuho Nakajima, Yukiko Sekine, Mika Tanaka, Kazuhiko Nakamura, Yasuhide Iwata, Kenji J. Tsuchiya, Norio Mori, Sevilla D. Detera-Wadleigh, Hironobu Ichikawa, Shigeyoshi Itohara, Takeo Yoshikawa, Teiichi Furuichi
J Clin Invest.
2007;
117(4):931–943
doi:10.1172/JCI29031
This article Copyright © 2007, The American Society for Clinical Investigation
Abstract
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A
utism, 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.
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