Ivan Jovanović1
1Institute of nuclear sciences ’’Vinča’’, National institite of the Republic of Serbia, Laboratory for radiobiology and molecular genetics, Mike Petrovića Alasa 12-14, 11001 Vinča, Beograd, Srbija
ivanj [at] vin.bg.ac.rs
Abstract
Rare copy number variants (CNVs) play a significant role in CAKUT development. However, the specific genetic drivers in certain CNVs associated with CAKUT remain unknown. To explore the genetic elements within CAKUT-associated CNVs, beyond the protein-coding genes, we leveraged the recently described comprehensive CNV landscape of CAKUT. MicroRNAs (miRNAs) are intriguing regulators of genomic networks and have the potential to be involved in CAKUT. Hereby, a pipeline for comprehensive analysis of miRNA genes affected by known, rare CNVs associated with CAKUT will be presented. The procedure is consisted of collection and synchronization of CNV regions specified in different hg assemblies with the hg19 assembly, mapping of the miRNA precursors, identification of the most frequently affected miRNAs and miRNA families by rare CNVs, bioinformatic interpretation of the top-rated miRNAs and prioritisation of key miRNAs for functional validation. Additionally, a method for estimation of the overall burden of rare CNVs on miRNA genes in CAKUT will be discussed. Remarkably, it was found that 80% of CAKUT patients with underlying rare CNV had at least one miRNA gene overlapping the identified CNV. Network analysis of the most frequently affected miRNAs has revealed the dominant regulation of the two miRNAs, hsa-miR-484 and hsa-miR-185-5p. Additionally, miR-548 family members have shown substantial enrichment in rare CNVs in CAKUT. The in vitro model which depicts the heterozygous deletion of the MIR484 has confirmed the study concept implying that rare CNVs affect the corresponding miRNA expression and subsequently dysregulatres miRNA target genes. The translational capacity of miRNA to be employed in therapeutic approaches is nowadays increasingly investigated. Therefore, the untangling of the mechanisms affected by dysregulated miRNAs could serve for future extension of genetic testing and the development of novel miRNA targeting strategies in CAKUT.
Keywords: CAKUT, CNV, miRNA.
Acknowledgement: This work was funded by the Science Fund of the Republic of Serbia, PROMIS, #6066923, miFaDriCa, and the Serbian Ministry of Education, Science, and Technological Development.
