Abstract: TH-PO986
DGKE Gene Variants in C3 Glomerulopathy
Session Information
- Pathology and Lab Medicine: Basic
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pathology and Lab Medicine
- 1501 Pathology and Lab Medicine: Basic
Authors
- Kumar, Ashwani, PGIMER, Chandigarh, India
- Ramachandran, Raja, Nehru Hospital, Chandigarh, India
- Duseja, Ritambhra Nada, Post Graduate Institute of Medical Education and Research, Chandigarh, India
Group or Team Name
- PGIMER
Background
DGKE is intra-cellular lipid kinases that phosphorylate the diacylglycerol (DAG) to phosphatidic acid (PA). Normal expression of DGKE is found in podocytes, endothelium, and platelets. Evidence of some variants of DGKE is reported in association with glomerular microangiopathies and found to have some overlapping feature with membranoproliferative glomerulonephritis (MPGN). As a pilot study, we screened patients of C3G in addition to alternative complement pathway related gene with focus on DGKE gene which confirmed its involvement in aHUS.
Methods
DNA from blood (EDTA) was isolated. Whole exome sequencing, clinical exome sequencing and targeted sequencing (15 genes; CFH, CFHR1, CFHR2, CFHR3, CFHR4, CFHR5, CD46, CFI, CFB, DGKE, C3, THBD, CFD, and properdin) were performed in 5 cases of C3GP. Test findings were analyzed and correlated with clinical outcome of these five patients.
Results
In addition to CFH and CFHR5 gene variants, whole exome sequencing in two cases revealed two variants in DGKE gene i.e. c.1583G>A (missense variants) and c.183G>A (synonymous variant) in case 1 whereas in case 2, only one variant c.579A>C (synonymous variant) was documented. Clinical exome sequencing was performed in case 3 which showed a variant in exon 6 of DGKE gene (c.998C>G). This variant is of undetermined significance that results in the amino acid substitution of Glycine for Alanine at codon 333 (p.Ala333Gly; ENTST00000284061). Targeted sequencing in other two patients showed c.579A>C (case 4) and c183G>A (case 5) variants in DGKE gene. Of 5 cases, case 1 and 2 are from the same family with the history of renal disease in the family. Case 1 expired and other receive a renal transplant. Case 3 had a history of UTI in childhood followed by MPGN on renal biopsy, which rapidly progressed to end-stage renal disease (ESRD)/underwent transplant and had graft failure in 16 months followed by graft nephrectomy. Patient 4 and 5 also had rapid progression to ESRD.
Conclusion
In present pilot study, the mutation/variants found in DGKE gene showed that genetic defects in C3G is not only limited to alternative complement pathway-related genes. Hence, we strongly recommend the screening of DGKE in all C3G patients. More data is needed to validate our findings.
Funding
- Government Support - Non-U.S.