Disruption of Diacylglycerol Kinase Delta (DGKD) Associated with Seizures in Humans and Mice

Department of Obstetrics, Gynecology, and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 05/2007; 80(4):792-9. DOI: 10.1086/513019
Source: PubMed


We report a female patient with a de novo balanced translocation, 46,X,t(X;2)(p11.2;q37)dn, who exhibits seizures, capillary abnormality, developmental delay, infantile hypotonia, and obesity. The 2q37 breakpoint observed in association with the seizure phenotype is of particular interest, because it lies near loci implicated in epilepsy in humans and mice. Fluorescence in situ hybridization mapping of the translocation breakpoints showed that no known genes are disrupted at Xp11.2, whereas diacylglycerol kinase delta (DGKD) is disrupted at 2q37. Expression studies in Drosophila and mouse suggest that DGKD is involved in central nervous system development and function. Electroencephalographic assessment of Dgkd mutant mice revealed abnormal epileptic discharges and electrographic seizures in three of six homozygotes. These findings implicate DGKD disruption by the t(X;2)(p11.2;q37)dn in the observed phenotype and support a more general role for DGKD in the etiology of seizures.

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    • "DGKϵ is uniformly expressed in brain, and its KO mice show an increased resistance to electroconvulsive and faster recovery than the wild type [46]. DGKδ is also associated to seizure, although its neuronal expression is very low: DGKδ gene is disrupted in a female patient with a de novo balanced translocation, who exhibits seizure with several dysfunctions, and electroencephalographic assessment of DGKδ mutant mice revealed abnormal epileptic discharges and electrographc seizures [40]. In addition, we also showed that seizure is severer in DGKβ KO mice than the wild type [31]. "
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    ABSTRACT: Diacylglycerol kinase (DGK) is a lipid kinase converting diacylglycerol to phosphatidic acid, and regulates many enzymes including protein kinase C, phosphatidylinositol 4-phosphate 5-kinase, and mTOR. To date, ten mammalian DGK subtypes have been cloned and divided into five groups, and they show subtype-specific tissue distribution. Therefore, each DGK subtype is thought to be involved in respective cellular responses by regulating balance of the two lipid messengers, diacylglycerol and phosphatidic acid. Indeed, the recent researches using DGK knockout mice have clearly demonstrated the importance of DGK in the immune system and its pathophysiological roles in heart and insulin resistance in diabetes. Especially, most subtypes show high expression in brain with subtype specific regional distribution, suggesting that each subtype has important and unique functions in brain. Recently, neuronal functions of some DGK subtypes have accumulated. Here, we introduce DGKs with their structural motifs, summarize the enzymatic properties and neuronal functions, and discuss the possibility of DGKs as a therapeutic target of the neuronal diseases.
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    • "Events modulated by DGKs include T-cell activation and anergy (Zha et al., 2006), synaptic vesicle fusion (McMullan et al., 2006; Yang et al., 2010), trafficking (Hasegawa et al., 2008; Los et al., 2006), and gene expression (7, 8). Further, disruption of specific DGKs has been linked to various pathologies (Fuchs et al., 2011; Leach et al., 2007; Regier et al., 2005; Rodriguez de Turco et al., 2001). It is clear, therefore, that understanding of how these enzymes are regulated is essential to understanding the regulation of the involved signaling pathways. "
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