Abstract
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.
Highlights
Dyslexia refers to a difficulty in reading and writing despite normal intelligence, senses, and adequate education
The authors show that an axon guidance receptor gene, ROBO1, is disrupted by a chromosomal translocation in one dyslexic individual; this study shows that the expression of ROBO1 is reduced on chromosomes from dyslexics in a large pedigree in which dyslexia has been linked to DYX5
We identified a patient who was diagnosed with both dyslexia and a translocation t(3;8)(p12;q11) involving the DYX5 region
Summary
Dyslexia refers to a difficulty in reading and writing despite normal intelligence, senses, and adequate education. The primary difficulty lies in phonological processing, rapid naming, and the recognition of phonemes [1]. Dyslexia is a common disorder, affecting 3% to 10% of the population [2]. Genome-wide screens have linked dyslexia to loci on Chromosomes 1p34–36 (DYX8), 2p16-p15 (DYX3), 3p12-q13 (DYX5), 6p21.3 (DYX2), 11p15.5 (DYX7), 15q21 (DYX1), 18p11.2 (DYX6), Xq27.3 (DYX9), and 7q32 The first dyslexia candidate susceptibility gene, DYX1C1 at 15q21, was recently identified, and a region corresponding to DYX2 has been narrowed down to a small number of candidate genes [12,13,14,15,16]
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