The Axon Guidance Receptor Gene <em>ROBO1</em> Is a Candidate Gene for Developmental Dyslexia

Dyslexia, or specific reading disability, is the most common learning disorder with a complex, partially genetic basis, but its biochemical mechanisms remain poorly understood. A locus on Chromosome 3, DYX5, has been linked to dyslexia in one large family and speech-sound disorder in a subset of small families. We found that the axon guidance receptor gene ROBO1, orthologous to the Drosophila roundabout gene, is disrupted by a chromosome translocation in a dyslexic individual. In a large pedigree with 21 dyslexic individuals genetically linked to a specific haplotype of ROBO1 (not found in any other chromosomes in our samples), the expression of ROBO1 from this haplotype was absent or attenuated in affected individuals. Sequencing of ROBO1 in apes revealed multiple coding differences, and the selection pressure was significantly different between the human, chimpanzee, and gorilla branch as compared to orangutan. We also identified novel exons and splice variants of ROBO1 that may explain the apparent phenotypic differences between human and mouse in heterozygous loss of ROBO1. We conclude that dyslexia may be caused by partial haplo-insufficiency for ROBO1 in rare families. Thus, our data suggest that a slight disturbance in neuronal axon crossing across the midline between brain hemispheres, dendrite guidance, or another function of ROBO1 may manifest as a specific reading disability in humans.阅读障碍（dyslexia），亦称特定阅读障碍（specific reading disability），是最为常见的学习障碍，其发病机制复杂且部分具有遗传基础，但目前其生化机制仍未得到充分阐明。3号染色体上的基因座（locus）DYX5曾在一个大型家系中被证实与阅读障碍相关，同时在部分小型家系中与言语语音障碍存在关联。本研究发现，轴突导向受体（axon guidance receptor）基因ROBO1——与果蝇roundabout基因同源——在一名阅读障碍患者体内因染色体易位（chromosome translocation）而发生结构破坏。在一个包含21名阅读障碍患者的大家系中，这些患者均与ROBO1的某一特定单倍型（haplotype）存在遗传关联，且该单倍型在我们的样本其余染色体上均未检出；患病个体中，源自该单倍型的ROBO1表达完全缺失或显著下调。对类人猿（apes）ROBO1的测序（sequencing）结果显示存在多处编码区差异（coding differences），且人类、黑猩猩（chimpanzee）与大猩猩（gorilla）分支所受的选择压力（selection pressure）与红毛猩猩（orangutan）分支存在显著差异。本研究还鉴定出了ROBO1的新型外显子（exons）与剪接变体（splice variants），这或可解释人类与小鼠在ROBO1杂合缺失（heterozygous loss）方面的表型差异（phenotypic differences）。综上，我们认为在罕见家系中，ROBO1的单倍剂量不足（haplo-insufficiency）可能引发阅读障碍。据此，我们的数据提示，神经元轴突跨大脑半球（brain hemispheres）中线过程、树突导向（dendrite guidance）或ROBO1的其他功能出现轻微紊乱，可能会导致人类出现特定阅读障碍。