title: The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia.
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.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Hannula-Jouppi
authors.forename: Nina
authors.initials: N
authors.lastname: Kaminen-Ahola
authors.forename: Mikko
authors.initials: M
authors.lastname: Taipale
authors.forename: Ranja
authors.initials: R
authors.lastname: Eklund
authors.forename: Jaana
authors.initials: J
authors.lastname: Nopola-Hemmi
authors.forename: Helena
authors.initials: H
authors.lastname: Kääriäinen
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002874:Chromosome Mapping; D004410:Dyslexia / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005192:Family Health; D020022:Genetic Predisposition to Disease; D006801:Humans; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology*; D009474:Neurons / Q000378:metabolism; D010375:Pedigree; D010802:Phylogeny; D011110:Polymorphism, Genetic; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology*; D013045:Species Specificity; D000097905:Roundabout Proteins
chemical_list: D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins