Approach to epigenetic analysis in language disorders

J Neurodevelop Disord Approach to epigenetic analysis in language disorders Shelley D. Smith 0 0 Supported by NIH-NICHD 5P50HD027802 to R.K. Olson and NIH: NIDCD R01 NIH0064386 to M.L. Rice 1 ) University of Nebraska Medical Center , Omaha, NE , USA Language and learning disorders such as reading disability and language impairment are recognized to be subject to substantial genetic influences, but few causal mutations have been identified in the coding regions of candidate genes. Association analyses of single nucleotide polymorphisms have suggested the involvement of regulatory regions of these genes, and a few mutations affecting gene expression levels have been identified, indicating that the quantity rather than the quality of the gene product may be most relevant for these disorders. In addition, several of the candidate genes appear to be involved in neuronal migration, confirming the importance of early developmental processes. Accordingly, alterations in epigenetic processes such as DNA methylation and histone modification are likely to be important in the causes of language and learning disorders based on their functions in gene regulation. Epigenetic processes direct the differentiation of cells in early development when neurological pathways are set down, and mutations in genes involved in epigenetic regulation are known to cause cognitive disorders in humans. Epigenetic processes also regulate the changes in gene expression in response to learning, and alterations in histone modification are associated with learning and memory deficits in animals. Genetic defects in histone modification have been reversed in animals through therapeutic interventions resulting in rescue of these deficits, making it particularly important to investigate their potential contribution to learning disorders in humans. Epigenetics; Dyslexia; Reading disability; Language impairment - Despite the complexity of language and learning disorders, individual genes are being defined which appear to influence the development of abilities that are necessary in speech, language, and reading. Most of the identified candidate genes involve reading disability, and although the evidence supporting some of these genes is still somewhat tenuous due to small sample sizes and limited replication, most are known to be involved in early development, particularly neuronal migration (Galaburda 2005; Gabel et al. 2010; Poelmans et al. 2011). As will be discussed below, most of these candidate genes have been associated with several learning and language phenotypes, suggesting that they facilitate learning processes which are basic to learning reading and language. Similar pleiotropic effects are seen for several genes that primarily affect autism or language but have also shown effects on reading, including CNTNAP2 and ATP2C2 (Vernes et al. 2008; Newbury et al. 2011). However, despite replicated evidence for association of single nucleotide polymorphisms within and around the genes, very few coding mutations have been reported to account for their influence on these disorders. This has led to the hypothesis that mutations affecting reading and related disorders are likely to be in regulatory regions, controlling the quantity rather than quality of the gene product (Bates et al. 2011). Alterations of gene expression can be caused by mutations in gene promoters and enhancers located near the gene, but mutations in genes that mediate epigenetic controls of gene expression have been found that affect developmental learning disorders. These mutations may be in regions located further from the target gene, making it more difficult to recognize their significance. Regulatory regions of genes influencing language and learning disorders Of all of the genes that have been proposed as candidates for reading disability and language impairment, six genes have been well characterized with respect to their influence on reading and language disorders, the regions within and around the genes that appear to contain causal mutations, and the effects of the putative mutations or risk alleles on gene transcription: DYX1C1, DCDC2, KIAA0319, ROBO1, and the co-regulated genes MRPL1 and C2ORF3. DYX1C1 The 15q21 region was identified as a candidate region for a gene or genes influencing reading disability (RD) through linkage studies (Fulker et al. 1991; Grigorenko et al. 1997), defining the DYX1 (DYsleXia-1st reported) locus. The DYX1C1 (DYX1-Candidate 1) gene was specifically targeted after a translocation t(2;15) (q11;q21) disrupting the previously uncharacterized gene was observed in a family with RD (Taipale et al. 2003). Since then, the DYX1C1 protein has been found to contain estrogen-receptor-binding sites (Massinen et al. 2009) and knockdown of the gene in embryonic rat brain produces delays in neuronal migration (Wang et al. 2006). Sequence analysis of the DYX1C1 coding regions identified a missense mutation in some RD families: rs57809907, 1249G> (...truncated)