DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN

J Am Soc Nephrol. 2013 Feb;24(3):377-84. doi: 10.1681/ASN.2012090903. Epub 2012 Dec 28.

Abstract

Renal microangiopathies and membranoproliferative GN (MPGN) can manifest similar clinical presentations and histology, suggesting the possibility of a common underlying mechanism in some cases. Here, we performed homozygosity mapping and whole exome sequencing in a Turkish consanguineous family and identified DGKE gene variants as the cause of a membranoproliferative-like glomerular microangiopathy. Furthermore, we identified two additional DGKE variants in a cohort of 142 unrelated patients diagnosed with membranoproliferative GN. This gene encodes the diacylglycerol kinase DGKε, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgkε colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGKε variants affect the intracellular concentration of diacylglycerol. Taken together, these results not only identify a genetic cause of a glomerular microangiopathy but also suggest that the phosphatidylinositol cycle, which requires DGKE, is critical to the normal function of podocytes.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cohort Studies
  • Consanguinity
  • DNA / genetics
  • Diacylglycerol Kinase / genetics*
  • Diacylglycerol Kinase / metabolism
  • Diagnosis, Differential
  • Diglycerides / metabolism
  • Female
  • Genetic Variation
  • Glomerulonephritis, Membranoproliferative / enzymology*
  • Glomerulonephritis, Membranoproliferative / genetics*
  • Glomerulonephritis, Membranoproliferative / pathology
  • HEK293 Cells
  • Humans
  • Kidney Diseases / enzymology*
  • Kidney Diseases / genetics*
  • Kidney Diseases / pathology
  • Kidney Glomerulus / enzymology
  • Male
  • Mice
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Podocytes / metabolism
  • Polymorphism, Single Nucleotide
  • Rats
  • Sequence Homology, Amino Acid
  • Turkey

Substances

  • Diglycerides
  • DNA
  • DGKE protein, human
  • Diacylglycerol Kinase