Anitha A, Nakamura Kazuhiko, Yamada Kazuo, Suda Shiro, Thanseem Ismail, Tsujii Masatsugu, Iwayama Yoshimi, Hattori Eiji, Toyota Tomoko, Miyachi Taishi, Iwata Yasuhide, Suzuki Katsuaki, Matsuzaki Hideo, Kawai Masayoshi, Sekine Yoshimoto, Tsuchiya Kenji, Sugihara Gen-Ichi, Ouchi Yasuomi, Sugiyama Toshiro, Koizumi Keita, Higashida Haruhiro, Takei Nori, Yoshikawa Takeo, Mori Norio
Department of Psychiatry and Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):1019-27. doi: 10.1002/ajmg.b.30697.
Autism is a pervasive developmental disorder diagnosed in early childhood. Abnormalities of serotonergic neurotransmission have been reported in autism. Serotonin transporter (SERT) modulates serotonin levels, and is a major therapeutic target in autism. Factors that regulate SERT expression might be implicated in the pathophysiology of autism. One candidate SERT regulatory protein is the roundabout axon guidance molecule, ROBO. SerT expression in Drosophila is regulated by robo; it plays a vital role in mammalian neurodevelopment also. Here, we examined the associations of ROBO3 and ROBO4 with autism, in a trio association study using DNA from 252 families recruited to AGRE. Four SNPs of ROBO3 (rs3923890, P = 0.023; rs7925879, P = 0.017; rs4606490, P = 0.033; and rs3802905, P = 0.049) and a single SNP of ROBO4 (rs6590109, P = 0.009) showed associations with autism; the A/A genotype of rs3923890 showed lower ADI-R_A scores, which reflect social interaction. Significant haplotype associations were also observed for ROBO3 and ROBO4. We further compared the mRNA expressions of ROBO1, ROBO2, ROBO3, and ROBO4 in the lymphocytes of 19 drug-naïve autistic patients and 20 age- and sex-matched controls. Expressions of ROBO1 (P = 0.018) and ROBO2 (P = 0.023) were significantly reduced in the autistic group; the possibility of using the altered expressions of ROBO as peripheral markers for autism, may be explored. In conclusion, we suggest a possible role of ROBO in the pathogenesis of autism. Abnormalities of ROBO may lead to autism either by interfering with serotonergic system, or by disrupting neurodevelopment. To the best of our knowledge, this is the first report relating ROBO with autism.
自闭症是一种在儿童早期被诊断出的广泛性发育障碍。已有报道称自闭症患者存在血清素能神经传递异常。血清素转运体（SERT）调节血清素水平，是自闭症的主要治疗靶点。调节SERT表达的因素可能与自闭症的病理生理机制有关。一种候选的SERT调节蛋白是轴突导向分子ROBO。果蝇中的SerT表达受robo调节；它在哺乳动物神经发育中也起着至关重要的作用。在此，我们在一项三联体关联研究中，使用从AGRE招募的252个家庭的DNA，研究了ROBO3和ROBO4与自闭症的关联。ROBO3的四个单核苷酸多态性（SNP，rs3923890，P = 0.023；rs7925879，P = 0.017；rs4606490，P = 0.033；以及rs3802905，P = 0.049）和ROBO4的一个单核苷酸多态性（rs6590109，P = 0.009）显示与自闭症有关联；rs3923890的A/A基因型显示出较低的ADI-R_A分数，该分数反映社交互动。还观察到ROBO3和ROBO4存在显著的单倍型关联。我们进一步比较了19名未用药的自闭症患者和20名年龄及性别匹配的对照者淋巴细胞中ROBO1、ROBO2、ROBO3和ROBO4的mRNA表达。自闭症组中ROBO1（P = 0.018）和ROBO2（P = 0.023）的表达显著降低；或许可以探索将ROBO表达改变用作自闭症外周标志物的可能性。总之，我们认为ROBO在自闭症发病机制中可能发挥作用。ROBO异常可能通过干扰血清素能系统或破坏神经发育导致自闭症。据我们所知，这是第一篇将ROBO与自闭症相关联的报道。
