Toncheva D, Mihailova-Hristova M, Vazharova R, Staneva R, Karachanak S, Dimitrov P, Simeonov V, Ivanov S, Balabanski L, Serbezov D, Malinov M, Stefanovic V, Čukuranović R, Polenakovic M, Jankovic-Velickovic L, Djordjevic V, Jevtovic-Stoimenov T, Plaseska-Karanfilska D, Galabov A, Djonov V, Dimova I
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.
Biomed Res Int. 2014;2014:920723. doi: 10.1155/2014/920723. Epub 2014 May 15.
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.
巴尔干地方性肾病（BEN）是一种家族性慢性肾小管间质性疾病，起病隐匿，进展缓慢，最终导致肾衰竭。分子生物学研究结果表明，BEN是一种多因素疾病，具有对环境风险因素的遗传易感性。使用Illumina Nextera外显子富集试剂盒对22个DNA样本（11名保加利亚患者和11名塞尔维亚患者）进行了22000个基因的外显子测序。通过NextGene、Provean和PolyPhen进行软件分析。将所有具有有害/损伤效应的注释基因变异的频率与欧洲人群的频率进行比较。然后我们关注未注释的变异（没有关于它们的数据，在健康的保加利亚对照中也未发现）。BEN患者的注释变异与欧洲人群之间没有统计学上的显著差异。从两组患者中频率超过40%的未注释变异中，我们提名了3个可能具有有害/损伤变异的基因——CELA1、HSPG2和KCNK5。BEN患者中的突变基因（CELA1、HSPG2和KCNK5）编码参与基底膜/细胞外基质和血管张力的蛋白质，这些蛋白质与血管生成过程紧密相关。我们认为血管生成异常过程在BEN的分子发病机制中起关键作用。
