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
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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)