Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients
Tetsushi Sadakata, … , Takeo Yoshikawa, Teiichi Furuichi
Tetsushi Sadakata, … , Takeo Yoshikawa, Teiichi Furuichi
Published April 2, 2007
Citation Information: J Clin Invest. 2007;117(4):931-943. https://doi.org/10.1172/JCI29031.
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Research Article

Autistic-like phenotypes in Cadps2-knockout mice and aberrant CADPS2 splicing in autistic patients

Abstract

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.

Authors

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

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Figure 10

Expression of exon 3–skipped CADPS2 mRNA in 2 pedigrees that include autistic patients.

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Expression of exon 3–skipped CADPS2 mRNA in 2 pedigrees that include aut...
(A and B) Pedigree structures (left) and patterns of agarose gel electrophoresis on the RT-PCR analysis of CADPS2 mRNA expressed in the blood of each individual (right). (A) Male monozygotic autistic twins (TW1 [autistic patient a5 shown in Figure 9A] and TW2 [autistic patient]) and their family members. A single major band (661 bp) produced by normal alternative splicing is apparent in their father (F); mother (M); older brother (B); and younger sister (S). On the other hand, an additional, 381-bp band produced by exon 3–skipped alternative splicing was expressed in both monozygotic autistic twins. (B) The autistic patient (patient a4 shown in Figure 9A), who expressed only the exon 3–skipped shorter band, and the patient’s family members. Similar to the family members in A, a single major band of 661 bp is expressed in the father and mother. M, molecular weight marker of the 100-bp ladder (from 200 bp at the bottom to 1000 bp at the top).