Abstract
Epileptic encephalopathies (EE) are severe epilepsy syndromes characterized by multiple seizure types, developmental delay and even regression. This class of disorders are increasingly being identified as resulting from de novo genetic mutations including many identified mutations in the family of chromodomain helicase DNA binding (CHD) proteins. In particular, several de novo pathogenic mutations have been identified in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2), a member of the sucrose nonfermenting (SNF-2) protein family of epigenetic regulators. These mutations in the CHD2 gene are causative of early onset epileptic encephalopathy, abnormal brain function, and intellectual disability. Our understanding of the mechanisms by which modification or loss of CHD2 cause this condition remains poorly understood. Here, we review what is known and still to be elucidated as regards the structure and function of CHD2 and how its dysregulation leads to a highly variable range of phenotypic presentations.
Highlights
Chromatin arrangement is a major functional aspect of transcriptional control and of the complex co-ordination of all body functions and systems in eukaryotes [1].Chromatin remodeling proteins constitute a large group of regulatory proteins which modulate the chromatin architecture and regulate temporal and spatial gene expression
In 1993 Delmas et al reported the discovery of a DNA-binding protein that contains both a chromo domain and a switch/sucrose non-fermenting (SWI/SNF) helicase domain that is present in most mammals
While mutations in most of the chromodomain helicase DNA binding (CHD) proteins have been described and demonstrated to lead to a range of cancers and developmental diseases (Table 1) [13,27,40,54,58,59,65,66,71], a number of gene variants in the gene encoding chromodomain helicase DNA binding protein 2 (CHD2) were identified as the cause of a developmental epileptic encephalopathy (CHD2-DEE) [16,17,18,19,20,21,73]
Summary
Chromatin arrangement is a major functional aspect of transcriptional control and of the complex co-ordination of all body functions and systems in eukaryotes [1]. Chromatin remodeling proteins constitute a large group of regulatory proteins which modulate the chromatin architecture and regulate temporal and spatial gene expression. They are unified by their capacity for coupling ATP hydrolysis to DNA conformational changes, thereby imparting direct control over RNA polymerase-mediated transcription [1,2,3,4]. Variants in the gene encoding the chromodomain helicase DNA binding protein 2 (CHD2) were identified as a cause of a rare developmental epileptic encephalopathy (DEE) [16,17,18,19,20,21]. We discuss how the canonical role of CHD2 may influence the variable phenotypic presentations of CHD2-developmental epileptic encephalopathy (CHD2-DEE), and the possibilities for future therapies to treat this complex disorder
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