Department of Radiobiology and Molecular Genetics, Vinča Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, P.O. Box 522, 11001, Belgrade, Serbia.
Nephrology and Urology Departments, University Children's Hospital, Belgrade, Serbia.
Pediatr Nephrol. 2024 Sep;39(9):2655-2665. doi: 10.1007/s00467-024-06381-x. Epub 2024 Apr 24.
Congenital anomalies of the kidney and urinary tract (CAKUT) represent a frequent cause of pediatric kidney failure. CNVs, as a major class of genomic variations, can also affect miRNA regions. Common CNV corresponding miRNAs (cCNV-miRNAs) are functional variants regulating crucial processes which could affect urinary system development. Thus, we hypothesize that cCNV-miRNAs are associated with CAKUT occurrence and its expressivity.
The extraction and filtering of common CNVs, identified in control samples deposited in publicly available databases gnomAD v2.1 and dbVar, were coupled with mapping of miRNA sequences using UCSC Genome Browser. After verification of the mapped miRNAs using referent miRBase V22.1, prioritization of cCNV-miRNA candidates has been performed using bioinformatic annotation and literature research. Genotyping of miRNA gene copy numbers for MIR9-3, MIR511, and MIR1299, was conducted on 221 CAKUT patients and 192 controls using TaqMan™ technology.
We observed significantly different MIR9-3 and MIR1299 gene copy number distribution between CAKUT patients and controls (Chi-square, P = 0.006 and P = 0.0002, respectively), while difference of MIR511 copy number distribution showed nominal significance (Chi-square, P = 0.027). The counts of less and more than two of MIR1299 copy numbers were more frequent within CAKUT patients compared to controls (P = 0.01 and P = 0.008, respectively) and also in cohort of patients with anomalies of the urinary tract compared to controls (P = 0.016 and P = 0.003, respectively).
Copy number variations of miRNA genes represent a novel avenue in clarification of the inheritance complexity in CAKUT and provide potential evidence about the association of common genetic variation with CAKUT phenotypes.
先天性肾和尿路异常（CAKUT）是小儿肾衰竭的常见原因。CNVs 作为基因组变异的主要类型，也可以影响 miRNA 区域。常见的 CNV 对应的 miRNA（cCNV-miRNAs）是调节关键过程的功能变异体，这些过程可能会影响泌尿系统的发育。因此，我们假设 cCNV-miRNAs 与 CAKUT 的发生及其表现度有关。
从 gnomAD v2.1 和 dbVar 等公共可用数据库中对照样本中提取和筛选常见的 CNVs，并使用 UCSC Genome Browser 映射 miRNA 序列。使用参考 miRBase V22.1 验证映射的 miRNA 后，使用生物信息学注释和文献研究对 cCNV-miRNA 候选物进行优先级排序。使用 TaqMan™ 技术对 221 名 CAKUT 患者和 192 名对照者的 MIR9-3、MIR511 和 MIR1299 基因拷贝数进行基因分型。
我们观察到 CAKUT 患者和对照组之间 MIR9-3 和 MIR1299 基因拷贝数分布有显著差异（卡方检验，P=0.006 和 P=0.0002），而 MIR511 拷贝数分布的差异具有名义显著性（卡方检验，P=0.027）。与对照组相比，CAKUT 患者中 MIR1299 拷贝数小于或大于两个的数量更为频繁（P=0.01 和 P=0.008），且在泌尿系统异常的患者中也更为频繁（P=0.016 和 P=0.003）。
miRNA 基因的拷贝数变异代表了阐明 CAKUT 遗传复杂性的新途径，并提供了常见遗传变异与 CAKUT 表型之间关联的潜在证据。
