The axon guidance receptor gene ROBO1 is a candidate gene for developmental dyslexia
Katariina Hannula-Jouppi, Nina Kaminen-Ahola, Mikko Taipale, Ranja Eklund, Jaana Nopola-Hemmi, Helena Kääriäinen, Juha Kere, Katariina Hannula-Jouppi, Nina Kaminen-Ahola, Mikko Taipale, Ranja Eklund, Jaana Nopola-Hemmi, Helena Kääriäinen, Juha Kere
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.
Conflict of interest statement
Competing interests. The authors have declared that no competing interests exist.
Figures
References
- Shaywitz SE. Dyslexia. N Engl J Med. 1998;338:307–312.
- Pennington BF. Annotation: The genetics of dyslexia. J Child Psychol Psychiatry. 1990;31:193–201.
- DeFries JC, Fulker DW, LaBuda MC. Evidence for a genetic etiology in reading disability of twins. Nature. 1987;329:537–539.
- Rabin M, Wen XL, Hepburn M, Lubs HA. Suggestive linkage of developmental dyslexia to chromosome 1p34–p36. Lancet. 1993;342:178.
- Cardon LR, Smith SD, Fulker DW, Kimberling WJ, Pennington BF, et al. Quantitative trait locus for reading disability on chromosome 6. Science. 1994;266:276–279.
- Grigorenko EL, Wood FB, Meyer MS, Hart LA, Speed WC, et al. Susceptibility loci for distinct components of developmental dyslexia on chromosomes 6 and 15. Am J Hum Genet. 1997;60:27–39.
- Fagerheim T, Raeymaekers P, Tonnessen FE, Pedersen M, Tranebjaerg L, et al. A new gene (DYX3) for dyslexia is located on chromosome 2. J Med Genet. 1999;36:664–669.
- Fisher SE, Francks C, Marlow AJ, MacPhie IL, Newbury DF, et al. Independent genome-wide scans identify a chromosome 18 quantitative-trait locus influencing dyslexia. Nature Genet. 2002;30:86–91.
- Kaminen N, Hannula-Jouppi K, Kestila M, Lahermo P, Muller K, et al. A genome scan for developmental dyslexia confirms linkage to chromosome 2p11 and suggests a new locus on 7q32. J Med Genet. 2003;40:340–345.
- de Kovel CG, Hol FA, Heister JG, Willemen JJ, Sandkuijl LA, et al. Genome-wide scan identifies susceptibility locus for dyslexia on Xq27 in an extended Dutch family. J Med Genet. 2004;41:652–657.
- Hsiung GY, Kaplan BJ, Petryshen TL, Lu S, Field L. A dyslexia susceptibility locus (DYX7) linked to dopamine D4 receptor (DRD4) region on chromosome 11p15.5. Am J Med Genet. 2004;125B:112–119.
- Fisher SE, DeFries JC. Developmental dyslexia: Genetic dissection of a complex cognitive trait. Nat Rev Neurosc. 2002;3:767–780.
- Taipale M, Kaminen N, Nopola-Hemmi J, Haltia T, Myllyluoma B, et al. A candidate gene for developmental dyslexia encodes a nuclear tetratricopeptide repeat domain protein dynamically regulated in brain. Proc Natl Acad Sci U S A. 2003;100:11553–11558.
- Cope N, Harold D, Hill G, Moskvina V, Stevenson J, et al. Strong evidence that KIAA0319 on chromosome 6p is a susceptibility gene for developmental dyslexia. Am J Hum Genet. 2005;76:581–591.
- Deffenbacher KE, Kenyon JB, Hoover DM, Olson RK, Pennington BF, et al. Refinement of the 6p21.3 quantitative trait locus influencing dyslexia: Linkage and association analyses. Hum Genet. 2004;115:128–138.
- Francks C, Paracchini S, Smith SD, Richardson AJ, Scerri TS, et al. A 77-kilobase region of chromosome 6p22.2 is associated with dyslexia in families from the United Kingdom and from the United States. Am J Hum Genet. 75:1046–1058.
- Nopola-Hemmi J, Myllyluoma B, Haltia T, Taipale M, Ollikainen V, et al. A dominant gene for developmental dyslexia on Chromosome 3. J Med Genet. 2001;38:658–664.
- Stein CM, Schick JH, Gerry Taylor H, Shriberg LD, Millard C, et al. Pleiotropic effects of a chromosome 3 locus on speech-sound disorder and reading. Am J Hum Genet. 2004;74:283–297.
- Nopola-Hemmi J, Myllyluoma B, Voutilainen A, Leinonen S, Kere J, et al. Familial dyslexia: Neurocognitive and genetic correlation in a large Finnish family. Dev Med Child Neurol. 2002;44:580–586.
- Kidd T, Brose K, Mitchell KJ, Fetter RD, Tessier-Lavigne M, et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell. 1998;92:205–215.
- Kidd T, Bland KS, Goodman CS. Slit is the midline repellent for the robo receptor in Drosophila . Cell. 1999;96:785–794.
- Seeger M, Tear G, Ferres-Marco D, Goodman CS. Mutations affecting growth cone guidance in Drosophila: Genes necessary for guidance toward or away from the midline. Neuron. 1993;10:409–426.
- Dallol A, Forgacs E, Martinez A, Sekido Y, Walker R, et al. Tumour specific promoter region methylation of the human homologue of the Drosophila Roundabout gene DUTT1 (ROBO1) in human cancers. Oncogene. 2002;21:3020–3028.
- Yan H, Yuan W, Velculescu VE, Vogelstein B, Kinzler KW, et al. Allelic variation in human gene expression. Science. 2002;297:1143.
- Pagani F, Baralle FE. Genomic variants in exons and introns: Identifying the splicing spoilers. Nature Rev. 2004;5:389–396.
- Clark AG, Glanowski S, Nielsen R, Thomas PD, Kejariwal A, et al. Inferring non-neutral evolution from human-chimp-mouse orthologous gene trios. Science. 2003;302:1960–1963.
- Enard W, Przeworski M, Fisher SE, Lai CS, et al. Molecular evolution of FOXP2, a gene involved in speech and language. Nature. 2002;418:869–872.
- Sundaresan V, Chung G, Heppell-Parton A, Xiong J, Grundy C, et al. Homozygous deletions at 3p12 in breast and lung cancer. Oncogene. 1998;17:1723–1729.
- Xian J, Aitchison A, Bobrow L, Corbett G, Pannell R, et al. Targeted disruption of the 3p12 gene, Dutt1/Robo1, predisposes mice to lung adenocarcinomas and lymphomas with methylation of the gene promoter. Cancer Res. 2004;64:6432–6437.
- Petek E, Windpassinger C, Simma B, Mueller T, Wagner K, et al. Molecular characterisation of a 15 Mb constitutional de novo interstitial deletion of chromosome 3p in a boy with developmental delay and congenital anomalies. J Hum Genet. 2003;48:283–287.
- Bashaw GJ, Kidd T, Murray D, Pawson T, Goodman CS. Repulsive axon guidance: Abelson and enabled play opposing roles downstream of the Roundabout receptor. Cell. 2000;101:703–715.
- Stein E, Tessier-Lavigne M. Hierarchical organization of guidance receptors: Silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science. 2001;291:1928–1938.
- Di Cristo G, Berardi N, Cancedda L, Pizzorusso T, Putignano E, et al. Requirement of ERK activation for visual cortical plasticity. Science. 2001;292:2337–2340.
- Sgambato V, Vanhoutte P, Pages C, Rogard M, Hipskind R, et al. In vivo expression and regulation of Elk-1, a target of the extracellular regulated kinase signaling pathway, in the adult rat brain. J Neurosci. 1998;18:214–226.
- Cammarota M, Bevilaqua LR, Ardenghi P, Paratcha G, Levi de Stein M, et al. Learning-associated activation of nuclear MAPK, CREB, and Elk-1, along with Fos production, in the rat hippocampus after a one-trial avoidance learning: Abolition by NMDA receptor blockade. Brain Res Mol Brain Res. 2000;76:36–46.
- Berman DE. Modulation of taste-induced Elk-1 activation by identified neurotransmitter systems in the insular cortex of the behaving rat. Neurobiol Learn Mem. 2003;79:122–126.
- Chapman NH, Igo RP, Thomson JB, Matsushita M, Brkanac Z, et al. Linkage analyses of four regions previously implicated in dyslexia: Confirmation of a locus on chromosome 15q. Am J Med Genet B Neuropsychiatr Genet. 2004;131B:67–75.
- Scerri TS, Fisher SE, Francks C, MacPhie IL, Paracchini S, et al. Putative functional alleles of DYX1C1 are not associated with dyslexia susceptibility in a large sample of sibling pairs from the UK. J Med Genet. 2004;41:853–857.
- Wigg KG, Couto JM, Feng Y, Anderson B, Cate-Carter TD, et al. Support for EKN1 as the susceptibility locus for dyslexia on 15q21. Mol Psychiatry. 2004;9:1111–1121.
- Cope NA, Hill G, van den Bree M, Harold D, Moskvina V, et al. No support for association between dyslexia susceptibility 1 candidate 1 and developmental dyslexia. Mol Psychiatry. 2005;10:237–238.
- Marino C, Giorda R, Lorusso ML, Vanzin L, Salandi N, et al. A family-based association study does not support DYX1C1 on 15q21.3 as a candidate gene in developmental dyslexia. Eur J Hum Genet. 2005;13:491–499.
- Meng H, Hager K, Held M, Page GP, Olson RK, et al. TDT-association analysis of EKN1 and dyslexia in a Colorado twin cohort. Hum Genet. 2005. Epub ahead of print. PMID: 16133186.
- Whitford KL, Marillat V, Stein E, Goodman CS, Tessier-Lavigne M, et al. Regulation of cortical dendrite development by Slit-Robo interactions. Neuron. 2002;33:47–61.
- Furrer MP, Kim S, Wolf B, Chiba A. Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline. Nat Neurosci. 2003;6:223–230.
- Aruga J, Yokota N, Mikoshiba K. Human SLITRK family genes: Genomic organization and expression profiling in normal brain and brain tumor tissue. Gene. 2003a;315:87–94.
- Aruga J, Mikoshiba K. Identification and characterization of Slitrk, a novel neuronal transmembrane protein family controlling neurite outgrowth. Mol Cell Neurosci. 2003b;24:117–129.
- Duret L, Mouchiroud D. Determinants of substitution rates in mammalian genes: Expression pattern affects selection intensity but not mutation rate. Mol Biol Evol. 2000;17:68–70.
- Dorus S, Vallender EJ, Evans PD, Anderson JR, Gilbert SL, et al. Accelerated evolution of nervous system genes in the origin of Homo sapiens . Cell. 2004;119:1027–1040.
- Häyrinen T, Serenius-Sirve S, Korkman M. Reading and writing test designed for and normated in Finnish elementary school (in Finnish) 1999. Psykologien kustannus Oy, Helsinki.
- Leinonen S, Müller K, Leppänen P, Aro M, Ahonen T, et al. Heterogeneity in adult dyslexic readers: Relating processing skills to the speed and accuracy of oral text reading. Read Writ Interdisc J. 2001;14:265–296.
- Wechsler D. Wechsler adult intelligence scale revised (WAIS-R) 1992. Psykologien kustannus Oy and The psychological corporation USA, Helsinki.
- Wechsler D. Wechsler intelligence scale for children revised (WISC-R) 1984. Psykologien kustannus Oy and The psychological corporation USA, Helsinki.
- Pastinen T, Sladek R, Gurd S, Sammak A, Ge B, et al. A survey of genetic and epigenetic variation affecting human gene expression. Physiol Genomics. 2003;16:184–193.
Source: PubMed