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Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.

ABSTRACT: 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.

SUBMITTER: Leach NT

PROVIDER: S-EPMC1852716 | biostudies-literature | 2007 Apr

REPOSITORIES: biostudies-literature

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Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.

Leach Natalia T NT Sun Yi Y Michaud Sebastien S Zheng Yi Y Ligon Keith L KL Ligon Azra H AH Sander Thomas T Korf Bruce R BR Lu Weining W Harris David J DJ Gusella James F JF Maas Richard L RL Quade Bradley J BJ Cole Andrew J AJ Kelz Max B MB Morton Cynthia C CC

American journal of human genetics 20070212 4

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 diac ...[more]

PMID: 17357084

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Project description:Background and aim: Diacylglycerol kinase (DGK) isoforms catalyze an enzymatic reaction that removes diacylglycerol (DAG) and thereby terminates protein kinase C (PKC) signaling by converting DAG to phosphatidic acid (PA). We have reported that downregulation of DGKδ (type II isozyme) causes peripheral insulin resistance, metabolic inflexibility, and obesity. Our aim was to determine whether overexpression of DGKδ protects against the development of metabolic impairments and obesity. Methods: We generated a transgenic mouse model overexpressing the human DGKδ2 isoform under the myosin light change promoter (DGKδ TG). We performed deep metabolic phenotyping of DGKδ TG and wild-type mice fed chow or high-fat diet. Mice were also given free access to running wheels to examine the effects of DGKδ overexpression on exercise-induced metabolic outcomes. Results: DGKδ TG mice were leaner than wild-type littermates, with improved glucose tolerance, increased glycogen storage in skeletal muscle, and enhanced glucose uptake in white adipose tissue. Moreover, DGKδ TG mice were protected against high fat diet (HFD)-induced glucose intolerance and obesity. DGKδ TG mice had reduced epididymal fat pad weight, and enhanced lipolysis. Strikingly, DGKδ overexpression recapitulates the beneficial effects exercise on metabolic outcomes. DGKδ overexpression and exercise have a synergistic effect on body weight reduction. Microarray analysis of skeletal muscle confirmed an overlap between genes associated with exercise and DGKδ overexpression. Gene ontology signatures of exercise and DGKδ overexpression were related to lipid storage, extracellular matrix, and glycogen biosynthesis pathways. Conclusion: We identify a role for DGKδ in glucose and energy homeostasis. Overexpression of DGKδ induces adaptive changes in both skeletal muscle and adipose tissue, resulting in protection against high fat diet-induced obesity. DGKδ overexpression recapitulates exercise-induced adaptations on energy homeostasis and skeletal muscle gene expression profiles.

Dataset Information

Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.

Publications

Disruption of diacylglycerol kinase delta (DGKD) associated with seizures in humans and mice.

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