Neurological diseases, including intellectual disability (ID), can be caused by disturbances in epigenetic regulation of specific genes that encode proteins necessary for appropriate central nervous system functioning. The “epigenetically caused” diseases can be due to the imprinting defects formed during germinal cells development or gained throughout life as a somatic changes. They can also result from abnormal functioning of transcriptional machinery caused by mutations in genes coding for specific proteins. Two most classical examples of disease caused by imprinting defect in germinal cells are Prader-Willi and Angelman syndromes, both characterized by ID and developmental delay. Both these diseases are caused by altered epigenetic regulation of genes localized on chromosome 15 (region q11–q13) that can be due to chromosome deletion or uniparental disomy. The other neurological disease that is related to abnormal epigenetic regulation is Fragile X syndrome characterized by ID and specific behavior. Almost all disease cases are due to the expansion of CGG repeat (>200) in the 5’UTR of FMR1 gene that leads to promoter methylation and lack of FMRP protein that is indispensable for neuron development and signaling. The example of neurological “epigenetic diseases” caused by altered transcriptional regulation is Rett syndrome caused by the mutation presence in MECP2 gene or its variant – Rett-like syndrome caused by the mutation in CDKL5 gene. Both these diseases are characterized by ID and childhood epilepsy. Herein, we present our experience from the research and diagnosis of above mentioned disorders in the context of neurological pathways altered by improper epigenetic regulation.
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Genomic imprinting is a normal process causing genes to be expressed from only one of the two parental chromosome homologues according to their parental origin. Imprinted genes function in a range of developmental processes. In recent years, data has emerged indicating discordance of imprinting between mouse and man, polymorphic imprinting between different individuals and tissue-specific imprinting within individuals. This suggests that imprinting might be an adaptable and dynamic process with the potential to act as a mechanism regulating gene dosage in different developmental contexts. Delta-like homologue 1 (Dlk1) is a paternally expressed imprinted gene that encodes both a transmembrane protein and a secreted isoform generated by alternative splicing, and is an atypical member of the Notch/Delta/Serrate family of developmental signalling molecules. Although widely expressed during embryonic development, only a few tissues including neurogenic regions of the brain retain Dlk1 expression in adults. Analysis of neurogenesis in the SVZ of Dlk1 mutant mice shows a reduction in the numbers of stem cells in vivo and an impairment of newborn neurons incorporated into the olfactory bulb as well as fewer primary neurospheres in vitro suggesting that normal levels of Dlk1 are necessary for the life-long maintenance of neural stem cells (NSCs). Within the SVZ, DLK1 is a niche factor secreted by astrocytes and that membrane-bound DLK1 is required in NSCs to respond to it. In contrast to the neighbouring Gtl2 gene, we observe specific absence of Dlk1 imprinting in the stem cell and astrocyte populations in the SVZ niche indicating that the mechanism conferring biallelic expression can override the imprint selectively at Dlk1 to control normal neurogenesis in the adult brain. This neurogenic requirement for both the maternally and paternally expressed alleles of the canonically imprinted Dlk1 gene supports the hypothesis that control of gene dosage by absence of imprinting is an important developmental process. We are testing the hypothesis that other imprinted genes important in neurogenesis may also modulate imprinting to control gene dosage.
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