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Yayınlanmış 1 Ocak 2013 | Sürüm v1
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DGKE Variants Cause a Glomerular Microangiopathy That Mimics Membranoproliferative GN

Yazarlar/Oluşturanlar

  • 1. Univ Texas SW Med Ctr Dallas, Dept Internal Med, Dallas, TX 75390 USA
  • 2. Gazi Univ, Fac Med, Dept Pediat Nephrol, Ankara, Turkey
  • 3. Gazi Univ, Fac Med, Dept Pathol, Ankara, Turkey
  • 4. Hacettepe Univ, Fac Med, Dept Pediat Nephrol, Nephrogenet Lab, TR-06100 Ankara, Turkey
  • 5. Hacettepe Univ, Fac Med, Dept Pediat Nephrol & Rheumatol, TR-06100 Ankara, Turkey
  • 6. Univ Texas SW Med Ctr Dallas, Dept Immunol, Dallas, TX 75390 USA
  • 7. Ohio State Univ, Coll Med, Columbus, OH 43210 USA

Açıklama

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 DGK epsilon, which is an intracellular lipid kinase that phosphorylates diacylglycerol to phosphatidic acid. Immunofluorescence confocal microscopy demonstrated that mouse and rat Dgk epsilon colocalizes with the podocyte marker WT1 but not with the endothelial marker CD31. Patch-clamp experiments in human embryonic kidney (HEK293) cells showed that DGK epsilon 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. J Am Soc Nephrol 24: 377-384, 2013. doi: 10.1681/ASN.2012090903

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