Alternative titles; symbols
HGNC Approved Gene Symbol: DGKE
Cytogenetic location: 17q22 Genomic coordinates (GRCh38) : 17:56,834,151-56,869,567 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q22 | {Hemolytic uremic syndrome, atypical, susceptibility to, 7} | 615008 | Autosomal recessive | 3 |
| Nephrotic syndrome, type 7 | 615008 | Autosomal recessive | 3 |
The DGKE gene encodes diacylglycerol kinase-epsilon, an intracellular lipid kinase that phosphorylates diacylglycerol (DAG) to phosphatidic acid. DGKE is the smallest of the known mammalian DGKs and lacks extra-enzymatic regulatory domains, suggesting that it is constitutively active (summary by Ozaltin et al., 2013).
See 125855 for a general discussion of the diacylglycerol kinases.
In a search for diacylglycerol kinase genes in humans, Tang et al. (1996) designed degenerate PCR primers based on conserved DGK catalytic domains to amplify products from a human endothelial cell cDNA library. A product with a novel sequence was identified and used to clone a 2.6-kb cDNA from an endothelial cell library. They named this gene DGK-epsilon. The cDNA encoded a 567-amino acid polypeptide with a predicted molecular weight of 64 kD. The catalytic region of DGK-epsilon shares 38 to 42% sequence identity with other DGKs, including DGK-alpha (125855) and DGK-delta (601207). When expressed in mammalian cells, DGK-epsilon showed specificity for arachidonyl-containing diacylglycerol. Northern blot analysis demonstrated that DGK-epsilon is expressed predominantly in testis.
Using immunofluorescence microscopy, Ozaltin et al. (2013) demonstrated that mouse and rat Dgke colocalized with the podocyte marker WT1 (607102), but not with the endothelial marker CD31 (173445). Western blot analysis confirmed these findings.
By protein blotting, Lemaire et al. (2013) found expression of DGKE in human endothelial cells and in the cytoplasmic and membrane fractions of platelets, 2 major cell types involved in thrombosis. DGKE was also expressed in the endothelium of glomerular capillaries and podocytes in human kidney.
By fluorescence in situ hybridization and radiation hybrid analysis, Hart et al. (1999) mapped the DGKE gene to chromosome 17q22.
Nephrotic Syndrome, Type 7
By homozygosity mapping combined with whole-exome analysis of a consanguineous family with early-onset nephrotic syndrome type 7 (NPHS7; 615008) and membranoproliferative glomerulonephritis on renal biopsy, Ozaltin et al. (2013) identified a homozygous truncating mutation in the DGKE gene (Q43X; 601440.0001). Sequencing of this gene in 142 unrelated patients with a similar disorder identified 2 more consanguineous families with different homozygous truncating mutations (601440.0002 and 601440.0003). Patients had onset of nephrotic syndrome with proteinuria usually in the first decade of life. The disorder was progressive, and some patients developed end-stage renal disease within several years. DGKE metabolizes and decreases intracellular DAG levels, thus contributing to the regulation of DAG levels. TRPC6 (603652) is a calcium-permeable cation channel expressed in the foot processes of podocytes and is known to be directly activated by DAG. In vitro functional expression studies in HEK293 cells showed that the DGKE mutants did not cause a decrease in TRPC6 current, as was observed with wildtype DGKE, consistent with a loss of DGKE function. The findings indicated that DGKE controls the intracellular concentration of DAG, which is a component of the phosphatidylinositol cycle that participates in multiple cellular functions and in lipid-mediated intracellular signaling. Perturbation of this pathway in podocytes may underlie the disorder.
Hemolytic Uremic Syndrome, Atypical, Susceptibility to
In 13 patients from 9 families with early-onset atypical hemolytic uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified homozygous or compound heterozygous mutations in the DGKE gene (see, e.g., 601440.0004-601440.0008). The disorder was characterized by acute onset in the first year of life of microangiopathic hemolytic anemia, thrombocytopenia, and renal failure. After the acute episodes, most patients developed chronic kidney disease. The first mutations in 4 patients from 2 families were found by exome sequencing. Sequencing the DGKE gene in 47 additional unrelated probands with pediatric-onset aHUS and 36 adult-onset aHUS probands, in whom there was no mutation in known aHUS-associated genes or CFH antibodies, identified 6 additional pediatric index cases carrying rare homozygous or compound heterozygous DGKE variants. Another family with 3 affected individuals was identified independently. The mutations included 3 premature termination codons, 2 frameshift mutations, 1 splice site mutation, and 2 missense mutations that altered conserved residues. DGKE was a frequent cause of aHUS in the first year of life (13 (27%) of 49 cases with aHUS) and accounted for 50% of familial disease in this age group (3 of 6 kindreds). This uniformly early age of onset defined a distinct subgroup of aHUS. Renal biopsy of 1 patient showed no DGKE expression, suggesting that loss of DGKE function is the underlying mechanism. Lemaire et al. (2013) noted that DGKE phosphorylates and inactivates arachidonic acid-containing diacylglycerol (AA-DAG) to the corresponding phosphatidic acid. AA-DAG is major signaling molecule that activates protein kinase C (PKC). PKC, in turn, increases the production of various prothrombotic factors in endothelial cells. Thus, loss of DGKE may result in sustained AA-DAG signaling, causing a prothrombotic state. In addition, DAGs modify slit diaphragm function in podocytes, a disturbance of which is consistent with renal-specific effects. The findings were important because this was the first genetic cause of aHUS not related to defects in genes encoding proteins in the complement cascade pathway.
In 4 sibs, born of consanguineous Turkish parents, with nephrotic syndrome type 7 (NPHS7; 615008), Ozaltin et al. (2013) identified a homozygous 127C-T transition in exon 2 of the DGKE gene, resulting in a gln43-to-ter (Q43X) substitution that results in a truncated protein missing all the functional domains. The mutation was identified using a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing. The unaffected parents were heterozygous for the mutation, which was not found in 332 control chromosomes or in several large databases. In vitro functional expression studies showed that the mutation resulted in a loss of function with an inability to regulate DAG levels properly in podocytes.
In 2 sibs, born of consanguineous Turkish parents, with nephrotic syndrome type 7 (NPHS7; 615008), Ozaltin et al. (2013) identified a 1-bp deletion (610delA) in exon 2 of the DGKE gene, resulting in a frameshift and premature termination (Thr204GlnfsTer6). The unaffected parents was heterozygous for the mutation. A heterozygous 610delA allele was found in 1 individual in the 1000 Genomes Project, but was not present in 6,503 samples of another exome database, yielding an allele frequency of 0.0002.
In 3 sibs, born of consanguineous parents of Lebanese origin, with nephrotic syndrome type 7 (NPHS7; 615008), Ozaltin et al. (2013) identified a homozygous A-to-G transition in intron 5 of the DGKE gene (889-2A-G) resulting in the production of an abnormal transcript predicted to create a premature stop codon (W350X). The abnormal transcript was subject to nonsense-mediated mRNA decay. The unaffected parents were heterozygous for the mutation, which was not found in 332 control chromosomes or in several large databases.
In 2 sibs of European ancestry with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified a homozygous c.966G-A transition in the DGKE gene, resulting in a trp322-to-ter (W322X) substitution in the kinase catalytic domain. The mutations were found by exome sequencing. Two additional patients with the disorder were also found to be homozygous for the W322X mutation, and haplotype analysis of the 3 families indicated a founder effect. Two further patients with a similar disorder carried the W322X mutation in compound heterozygosity with another mutation in the DGKE gene (see, e.g., S11X, 601440.0007). The W322X mutation was found in heterozygous state in 1 of 8,475 controls of European ancestry.
In 2 sibs with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified compound heterozygous mutations in the DGKE gene: a 1-bp insertion (c.486insA), resulting in a frameshift and premature termination (Val163SerfsTer3) in a C1 domain that binds DAG, and a c.188G-C transversion, resulting in an arg63-to-pro (R63P; 601440.0006) substitution at a conserved residue in a C1 domain that binds DAG. Neither mutation was found in 8,475 control subjects. No functional studies of the mutations were performed.
For discussion of the arg63-to-pro (R63P) mutation in the DGKE gene that was found in compound heterozygous state in 2 sibs with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008) by Lemaire et al. (2013), see 601440.0005.
In a patient with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified compound heterozygous mutations in the DGKE gene: a c.32C-A transversion, resulting in a ser11-to-ter (S11X) substitution in the N-terminal region, and W322X (601440.0004). The S11X mutation was not found in 8,475 control subjects.
In 3 German sibs, born of consanguineous parents, with atypical hemolytic-uremic syndrome-7 (AHUS7; see 615008), Lemaire et al. (2013) identified a homozygous c.818G-C transversion in the DGKE gene, resulting in an arg273-to-pro (R273P) substitution at a highly conserved residue in the catalytic kinase domain. The mutation was not found in 8,475 control subjects. No functional studies were performed.
Hart, T. C., Price, J. A., Bobby, P. L., Pettenati, M. J., Shashi, V., Von Kap Herr, C., Van Dyke, T. E. Cytogenetic assignment and physical mapping of the human DGKE gene to chromosome 17q22. Genomics 56: 233-235, 1999. [PubMed: 10051413] [Full Text: https://doi.org/10.1006/geno.1998.5624]
Lemaire, M., Fremeaux-Bacchi, V., Schaefer, F., Choi, M., Tang, W. H., Le Quintrec, M., Fakhouri, F., Taque, S., Nobili, F., Martinez, F., Ji, W., Overton, J. D., and 18 others. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nature Genet. 45: 531-536, 2013. [PubMed: 23542698] [Full Text: https://doi.org/10.1038/ng.2590]
Ozaltin, F., Li, B., Rauhauser, A., An, S.-W., Soylemezoglu, O., Gonul, I. I., Taskiran, E. Z., Ibsirlioglu, T., Korkmaz, E., Bilginer, Y., Duzova, A., Ozen, S., and 21 others. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J. Am. Soc. Nephrol. 24: 377-384, 2013. [PubMed: 23274426] [Full Text: https://doi.org/10.1681/ASN.2012090903]
Tang, W., Bunting, M., Zimmerman, G. A., McIntyre, T. M., Prescott, S. M. Molecular cloning of a novel human diacylglycerol kinase highly selective for arachidonate-containing substrates. J. Biol. Chem. 271: 10237-10241, 1996. [PubMed: 8626589]