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Biomed Res Int. 2014;2014:920723. doi: 10.1155/2014/920723. Epub 2014 May 15.

NGS nominated CELA1, HSPG2, and KCNK5 as candidate genes for predisposition to Balkan endemic nephropathy.

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Department of Medical Genetics, Medical University of Sofia, Zdrave Street 2, 1431 Sofia, Bulgaria ; Genomics Laboratory of Malinov Clinic, 1620 Sofia, Bulgaria.
Department of Medical Genetics, Medical University of Sofia, Zdrave Street 2, 1431 Sofia, Bulgaria.
Genomics Laboratory of Malinov Clinic, 1620 Sofia, Bulgaria.
Vratza District Hospital, 66 "Vtori Iuni" Boulevard, 3000 Vratza, Bulgaria.
Faculty of Medicine, University of Nis, Univerzitetski trg 2, 18000 Nis, Serbia.
Faculty of Medicine, University of Skopje, Macedonian Academy of Sciences and Arts, Bul. Krste Misirkov 2, P.O. Box 428, 1000 Skopje, Macedonia.
Institute of Microbiology, Bulgarian Academy of Sciences, 26 Georgi Bonchev Street, 1113 Sofia, Bulgaria.
National Center of Public Health and Analyses, 15 Acad. Ivan Evst. Geshov Boulevard, 1431 Sofia, Bulgaria.
Institute of Anatomy, Bern University, Baltzerstrass 2, 3012 Bern, Switzerland.


Balkan endemic nephropathy (BEN) is a familial chronic tubulointerstitial disease with insidious onset and slow progression leading to terminal renal failure. The results of molecular biological investigations propose that BEN is a multifactorial disease with genetic predisposition to environmental risk agents. Exome sequencing of 22 000 genes with Illumina Nextera Exome Enrichment Kit was performed on 22 DNA samples (11 Bulgarian patients and 11 Serbian patients). Software analysis was performed via NextGene, Provean, and PolyPhen. The frequency of all annotated genetic variants with deleterious/damaging effect was compared with those of European populations. Then we focused on nonannotated variants (with no data available about them and not found in healthy Bulgarian controls). There is no statistically significant difference between annotated variants in BEN patients and European populations. From nonannotated variants with more than 40% frequency in both patients' groups, we nominated 3 genes with possible deleterious/damaging variants--CELA1, HSPG2, and KCNK5. Mutant genes (CELA1, HSPG2, and KCNK5) in BEN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, tightly connected to process of angiogenesis. We suggest that an abnormal process of angiogenesis plays a key role in the molecular pathogenesis of BEN.

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