Dataset Information

Diacylglycerol Kinase-?: Properties and Biological Roles.

ABSTRACT: In mammals there are at least 10 isoforms of diacylglycerol kinases (DGK). All catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). Among DGK isoforms, DGK? has several unique features. It is the only DGK isoform with specificity for a particular species of DAG, i.e., 1-stearoyl-2-arachidonoyl glycerol. The smallest of all known DGK isoforms, DGK?, is also the only DGK devoid of a regulatory domain. DGK? is the only DGK isoform that has a hydrophobic segment that is predicted to form a transmembrane helix. As the only membrane-bound, constitutively active DGK isoform with exquisite specificity for particular molecular species of DAG, the functional overlap between DGK? and other DGKs is predicted to be minimal. DGK? exhibits specificity for DAG containing the same acyl chains as those found in the lipid intermediates of the phosphatidylinositol-cycle. It has also been shown that DGK? affects the acyl chain composition of phosphatidylinositol in whole cells. It is thus likely that DGK? is responsible for catalyzing one step in the phosphatidylinositol-cycle. Steps of this cycle take place in both the plasma membrane and the endoplasmic reticulum membrane. DGK? is likely present in both of these membranes. DGK? is the only DGK isoform that is associated with a human disease. Indeed, recessive loss-of-function mutations in DGK? cause atypical hemolytic-uremic syndrome (aHUS). This condition is characterized by thrombosis in the small vessels of the kidney. It causes acute renal insufficiency in infancy and most patients develop end-stage renal failure before adulthood. Disease pathophysiology is poorly understood and there is no therapy. There are also data suggesting that DGK? may play a role in epilepsy and Huntington disease. Thus, DGK? has many unique molecular and biochemical properties when compared to all other DGK isoforms. DGK? homologs also contain a number of conserved sequence features that are distinctive characteristics of either the rodents or specific groups of primate homologs. How cells, tissues and organisms harness DGK?'s catalytic prowess remains unclear. The discovery of DGK?'s role in causing aHUS will hopefully boost efforts to unravel the mechanisms by which DGK? dysfunction causes disease.

SUBMITTER: Epand RM

PROVIDER: S-EPMC5067486 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Diacylglycerol Kinase-ε: Properties and Biological Roles.

Epand Richard M RM So Vincent V Jennings William W Khadka Bijendra B Gupta Radhey S RS Lemaire Mathieu M

Frontiers in cell and developmental biology 20161018

In mammals there are at least 10 isoforms of diacylglycerol kinases (DGK). All catalyze the phosphorylation of diacylglycerol (DAG) to phosphatidic acid (PA). Among DGK isoforms, DGKε has several unique features. It is the only DGK isoform with specificity for a particular species of DAG, i.e., 1-stearoyl-2-arachidonoyl glycerol. The smallest of all known DGK isoforms, DGKε, is also the only DGK devoid of a regulatory domain. DGKε is the only DGK isoform that has a hydrophobic segment that is pr ...[more]

PMID: 27803897

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Project description:Recessive mutations in diacylglycerol kinase epsilon (DGKE) display genetic pleiotropy, with pathological features reported as either thrombotic microangiopathy or membranoproliferative glomerulonephritis (MPGN), and clinical features of atypical hemolytic uremic syndrome (aHUS), nephrotic syndrome or both. Pathophysiological mechanisms and optimal management strategies have not yet been defined. In prospective and retrospective studies of aHUS referred to the United Kingdom National aHUS service and prospective studies of MPGN referred to the National Registry of Rare Kidney Diseases for MPGN we defined the incidence of DGKE aHUS as 0.009/million/year and so-called DGKE MPGN as 0.006/million/year, giving a combined incidence of 0.015/million/year. Here, we describe a cohort of sixteen individuals with DGKE nephropathy. One presented with isolated nephrotic syndrome. Analysis of pathological features reveals that DGKE mutations give an MPGN-like appearance to different extents, with but more often without changes in arterioles or arteries. In 15 patients presenting with aHUS, ten had concurrent substantial proteinuria. Identified triggering events were rare but coexistent developmental disorders were seen in six. Nine with aHUS experienced at least one relapse, although in only one did a relapse of aHUS occur after age five years. Persistent proteinuria was seen in the majority of cases. Only two individuals have reached end stage renal disease, 20 years after the initial presentation, and in one, renal transplantation was successfully undertaken without relapse. Six individuals received eculizumab. Relapses on treatment occurred in one individual. In four individuals eculizumab was withdrawn, with one spontaneously resolving aHUS relapse occurring. Thus we suggest that DGKE-mediated aHUS is eculizumab non-responsive and that in individuals who currently receive eculizumab therapy it can be safely withdrawn. This has important patient safety and economic implications.

Dataset Information

Diacylglycerol Kinase-?: Properties and Biological Roles.

Publications

Diacylglycerol Kinase-ε: Properties and Biological Roles.

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