Genetic Analyses of Roundabout (ROBO) Axon Guidance Receptors in Autism
Genetic Analyses of Roundabout (ROBO) Axon Guidance Receptors in Autism
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DOI：
10.1002/ajmg.b.30697
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发表时间：
2008-10-05
影响因子：
2.8
通讯作者：
Mori, Norio
中科院分区：
文献类型：
--
作者：
Anitha, A.;Nakamura, Kazuhiko;Mori, Norio
自闭症是一种在儿童早期被诊断出的广泛性发育障碍。孤独症患者存在多巴胺能神经传递障碍。5-羟色胺转运体（SERT）调节5-羟色胺水平，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学有关。一种候选的SERT调节蛋白是迂回轴突引导分子ROBO。SerT在果蝇中的表达受robo调控，它在哺乳动物神经发育中也起着重要作用。在这里，我们研究了ROBO 3和ROBO 4与自闭症的关系，在一项三重关联研究中使用了来自AGRE招募的252个家庭的DNA。ROBO 3的四个SNP（rs3923890，P = 0.023; rs7925879，P = 0.017; rs 4606490，P = 0.033;和rs3802905，P = 0.049）和ROBO 4的单个SNP。（rs6590109，P = 0.009）显示与孤独症相关; rs3923890的A/A基因型显示较低的ADI-R_A得分，这反映了社会互动。还观察到ROBO 3和ROBO 4的显著单倍型关联。我们进一步比较了ROBO 1，ROBO 2，ROBO 3和ROBO 4在19名药物初治自闭症患者和20名年龄和性别匹配的对照组淋巴细胞中的mRNA表达。ROBO 1（P = 0.018）和ROBO 2（P = 0.023）的表达在自闭症组中显著降低;可以探索使用改变的ROBO表达作为自闭症的外周标记物的可能性。总之，我们认为ROBO在自闭症的发病机制中可能发挥作用。ROBO的缺失可能通过干扰多巴胺能系统或破坏神经发育而导致自闭症。据我们所知，这是第一份有关ROBO与自闭症的报告。(C)2008 Wiley-Liss，Inc.
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-naive 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. (C) 2008 Wiley-Liss, Inc.