title: DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN.
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.
authors.affiliation: Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Ankara, Turkey.
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.forename: Binghua
authors.initials: B
authors.lastname: Li
authors.forename: Alysha
authors.initials: A
authors.lastname: Rauhauser
authors.forename: Sung-Wan
authors.initials: SW
authors.lastname: An
authors.forename: Oguz
authors.initials: O
authors.lastname: Soylemezoglu
authors.forename: Ipek Isik
authors.initials: II
authors.lastname: Gonul
authors.forename: Ekim Z
authors.initials: EZ
authors.lastname: Taskiran
authors.forename: Tulin
authors.initials: T
authors.lastname: Ibsirlioglu
authors.forename: Emine
authors.initials: E
authors.lastname: Korkmaz
authors.forename: Yelda
authors.initials: Y
authors.lastname: Bilginer
authors.forename: Ali
authors.initials: A
authors.lastname: Duzova
authors.forename: Seza
authors.initials: S
authors.lastname: Ozen
authors.forename: Rezan
authors.initials: R
authors.lastname: Topaloglu
authors.forename: Nesrin
authors.initials: N
authors.lastname: Besbas
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.forename: Yong
authors.initials: Y
authors.lastname: Du
authors.forename: Chaoying
authors.initials: C
authors.lastname: Liang
authors.forename: Phylip
authors.initials: P
authors.lastname: Chen
authors.forename: Dongmei
authors.initials: D
authors.lastname: Lu
authors.forename: Komal
authors.initials: K
authors.lastname: Vadnagara
authors.forename: Susan
authors.initials: S
authors.lastname: Arbuckle
authors.forename: Deborah
authors.initials: D
authors.lastname: Lewis
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wakeland
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Quigg
authors.forename: Richard F
authors.initials: RF
authors.lastname: Ransom
authors.forename: Edward K
authors.initials: EK
authors.lastname: Wakeland
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Topham
authors.forename: Nicolas G
authors.initials: NG
authors.lastname: Bazan
authors.forename: Chandra
authors.initials: C
authors.lastname: Mohan
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
authors.forename: Aysin
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Chou-Long
authors.initials: CL
authors.lastname: Huang
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D015331:Cohort Studies; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D019852:Diacylglycerol Kinase / Q000235:genetics* / Q000378:metabolism; D003937:Diagnosis, Differential; D004075:Diglycerides / Q000378:metabolism; D005260:Female; D014644:Genetic Variation; D015432:Glomerulonephritis, Membranoproliferative / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D007674:Kidney Diseases / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D007678:Kidney Glomerulus / Q000201:enzymology; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D050199:Podocytes / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D017386:Sequence Homology, Amino Acid; D014421:Turkey
chemical_list: D004075:Diglycerides; D004247:DNA; C526464:DGKE protein, human; D019852:Diacylglycerol Kinase