41 In addition, a recent analysis of 2q23.1 microdeletion syndrome, which also shares similarities to autism, pinpointed MBD5 as the causative locus.42 Further association of MBD5 with autism has been shown via sequencing of autistic individuals with chromosomal abnormalities.43 Interestingly, three recent independent sequencing studies implicated another
gene involved in chromatin remodeling: chromodomain-helicase-DNA-binding protein 8 (CHD8).27,28,43 One study also identified de novo events in CHD3 and CHD7.28 Individuals with mutations in CHD7 develop CHARGE syndrome, 68% of whom exhibit an autistic-like phenotype.44 Inhibitors,research,lifescience,medical Furthermore, the histone methyltransferase EHMT1, which is responsible for another syndromic form of autism called Kleefstra’s syndrome,45 was Inhibitors,research,lifescience,medical identified in two of these studies.28,43 Another recent exome sequencing study of 343 simplex families identified 13 candidate genes involved in either transcription regulation or chromatin remodeling.30 As a whole, these findings suggest
that autism may arise as a result of impaired regulation of the chromatin state. Such selleck chemical dysregulation may result in improper Inhibitors,research,lifescience,medical synaptic wiring of brain circuitry and/or prevent the proper neuronal response from external stimuli necessary for the development of social cognition. Further analyses into the relationship between neuronal activity and chromatin remodeling are necessary to garner clues for how the two may orchestrate Inhibitors,research,lifescience,medical circuit formation. Large recurrent copy number variants (CNVs) have been associated with autism.46 Careful consideration of the molecular effects of such a genetic locus is
warranted. On first consideration, it is likely that the majority of such loci alter the dosage or gene expression level of a number of contiguous genes. Is one gene involved in these loci or is Inhibitors,research,lifescience,medical it a combination of genes? For the majority of CNVs, it seems most likely that the latter model will prevail, that CNVs lead to a complex interaction of the effects of perturbed gene expression from multiple contiguous genes. In some ways, the loss of a gene that modulates gene expression such a chromatin modifying gene may have similar effects, ie perturbation of dosage of a collection of genes. Pre-mRNA splicing Disruption of A2BP1/FOX1, a gene involved in mediating RNA splicing, has been noted in Drug_discovery two autistic individuals.47-48 This is especially intriguing in that another category of genes implicated in autism—cell adhesion molecules (CAMs)—exhibit selleck chemical Tofacitinib numerous alternatively spliced transcripts that appear crucial for cell-cell recognition.49 The aforementioned transcriptome analysis not only revealed A2BP1 to be downregulated in comparison to control tissue but also determined many of the protein’s targets were genes involved in synaptic function.