TY  - JOUR
AU  - Mitrović, Kristina
AU  - Životić, Ivan
AU  - Kolić, Ivana
AU  - Žakula, Jelena
AU  - Živković, Maja
AU  - Stanković, Aleksandra
AU  - Jovanović, Ivan
PY  - 2024
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12889
AB  - Background The majority of CAKUT-associated CNVs overlap at least one miRNA gene, thus affecting the cellular levels of the corresponding miRNA. We aimed to investigate the potency of restitution of CNV-affected miRNA levels to remediate the dysregulated expression of target genes involved in kidney physiology and development in vitro.  Methods Heterozygous MIR484 knockout HEK293 and homozygous MIR185 knockout HEK293 cell lines were used as models depicting the deletion of the frequently affected miRNA genes by CAKUT-associated CNVs. After treatment with the corresponding miRNA mimics, the levels of the target genes have been compared to the non-targeting control treatment. For both investigated miRNAs, MDM2 and PKD1 were evaluated as common targets, while additional 3 genes were investigated as targets of each individual miRNA (NOTCH3, FIS1 and APAF1 as hsa-miR-484 targets and RHOA, ATF6 and CDC42 as hsa-miR-185-5p targets).  Results Restitution of the corresponding miRNA levels in both knockout cell lines has induced a change in the mRNA levels of certain candidate target genes, thus confirming the potential to alleviate the CNV effect on miRNA expression. Intriguingly, HEK293 WT treatment with investigated miRNA mimics has triggered a more pronounced effect, thus suggesting the importance of miRNA interplay in different genomic contexts.  Conclusions Dysregulation of multiple mRNA targets mediated by CNV-affected miRNAs could represent the underlying mechanism behind the unresolved CAKUT occurrence and phenotypic variability observed in CAKUT patients. Characterizing miRNAs located in CNVs and their potential to become molecular targets could eventually help in understanding and improving the management of CAKUT.
T2  - BMC Genomics
T1  - A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT
VL  - 25
IS  - 1
SP  - 218
DO  - 10.1186/s12864-024-10121-8
ER  - 

@article{
author = "Mitrović, Kristina and Životić, Ivan and Kolić, Ivana and Žakula, Jelena and Živković, Maja and Stanković, Aleksandra and Jovanović, Ivan",
year = "2024",
abstract = "Background The majority of CAKUT-associated CNVs overlap at least one miRNA gene, thus affecting the cellular levels of the corresponding miRNA. We aimed to investigate the potency of restitution of CNV-affected miRNA levels to remediate the dysregulated expression of target genes involved in kidney physiology and development in vitro.  Methods Heterozygous MIR484 knockout HEK293 and homozygous MIR185 knockout HEK293 cell lines were used as models depicting the deletion of the frequently affected miRNA genes by CAKUT-associated CNVs. After treatment with the corresponding miRNA mimics, the levels of the target genes have been compared to the non-targeting control treatment. For both investigated miRNAs, MDM2 and PKD1 were evaluated as common targets, while additional 3 genes were investigated as targets of each individual miRNA (NOTCH3, FIS1 and APAF1 as hsa-miR-484 targets and RHOA, ATF6 and CDC42 as hsa-miR-185-5p targets).  Results Restitution of the corresponding miRNA levels in both knockout cell lines has induced a change in the mRNA levels of certain candidate target genes, thus confirming the potential to alleviate the CNV effect on miRNA expression. Intriguingly, HEK293 WT treatment with investigated miRNA mimics has triggered a more pronounced effect, thus suggesting the importance of miRNA interplay in different genomic contexts.  Conclusions Dysregulation of multiple mRNA targets mediated by CNV-affected miRNAs could represent the underlying mechanism behind the unresolved CAKUT occurrence and phenotypic variability observed in CAKUT patients. Characterizing miRNAs located in CNVs and their potential to become molecular targets could eventually help in understanding and improving the management of CAKUT.",
journal = "BMC Genomics",
title = "A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT",
volume = "25",
number = "1",
pages = "218",
doi = "10.1186/s12864-024-10121-8"
}

Mitrović, K., Životić, I., Kolić, I., Žakula, J., Živković, M., Stanković, A.,& Jovanović, I.. (2024). A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT. in BMC Genomics, 25(1), 218.
https://doi.org/10.1186/s12864-024-10121-8

Mitrović K, Životić I, Kolić I, Žakula J, Živković M, Stanković A, Jovanović I. A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT. in BMC Genomics. 2024;25(1):218.
doi:10.1186/s12864-024-10121-8 .

Mitrović, Kristina, Životić, Ivan, Kolić, Ivana, Žakula, Jelena, Živković, Maja, Stanković, Aleksandra, Jovanović, Ivan, "A preliminary study of the miRNA restitution effect on CNV-induced miRNA downregulation in CAKUT" in BMC Genomics, 25, no. 1 (2024):218,
https://doi.org/10.1186/s12864-024-10121-8 . .

TY  - CONF
AU  - Životić, Ivan
AU  - Mitrović, Kristina
AU  - Kolić, Ivana
AU  - Seke, Mariana
AU  - Živković, Maja
AU  - Stanković, Aleksandra
AU  - Jovanović, Ivan
PY  - 2023
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12465
AB  - Introduction: Congenital anomalies of the kidney and urinary tracts(CAKUT) are a diverse spectrum of defects with complex etiology and not fully explained genetic background. miRNA-containing copy number variants (CNVs) are described as genetic risk factor for the disease development. We aimed to identify miRNAs with the maximum regulatory coverage of previously reported differentially expressed genes in CAKUT tissue compared to controls and bioinformatically characterize a set of these miRNAs which are located in common CNVs. Methods: Differentially expressed genes were identified from ureter tissue transcriptome open data GSE83946 from 15 CAKUT patients and 7 healthy controls, generated in house previously. miRPathDB v2.0 was used for identification of miRNAs with maximum coverage of DEGs(miRNAs which complimentarily regulate all DEGs). Mapping of maximum coverage miRNAs onto common CNVs (frequency >0.2) was performed using UCSC genome browser and gnomAD database. miRNA mapping common CNVs were further bioinformatically analyzed using miRPathDB v2.0. Results: In a maximum coverage set of 50 miRNAs interacting with DEGs in CAKUT, we have identified 3 miRNA geneslocated in the common CNVs(hsa-miR-663b, hsa-miR-3180-3p and hsa-miR-1302). Using Reactome database we identified all three miRNAsto be significantly enriched in the pathway Neuronal System: -log(p-value)>2.326 for hsa-miR-1302; -log(p-value)>1.556 for hsa-miR-3180-3p; and -log(pvalue)>1.703 for hsa-miR-663b. Conclusion: CAKUT is characterized with variable penetrability and expressivity and often followed with other comorbiditiessuch as neurodevelopmental disorders. miRNAsinvolved in DEG networks and prone to CNV effects could present modulating factors of the disease phenotype. Further studies should provide additional evidence about hsa-miR-1302, hsa-miR-3180-3p and hsa-miR-663b involvements in CAKUT etiology
C3  - CoMBoS2 – the Second Congress of Molecular Biologists of Serbia : Book of abstracts
T1  - Identification of micro RNA from common copy number variants as risk factors for CAKUT
SP  - 62
EP  - 62
UR  - https://hdl.handle.net/21.15107/rcub_vinar_12465
ER  - 

@conference{
author = "Životić, Ivan and Mitrović, Kristina and Kolić, Ivana and Seke, Mariana and Živković, Maja and Stanković, Aleksandra and Jovanović, Ivan",
year = "2023",
abstract = "Introduction: Congenital anomalies of the kidney and urinary tracts(CAKUT) are a diverse spectrum of defects with complex etiology and not fully explained genetic background. miRNA-containing copy number variants (CNVs) are described as genetic risk factor for the disease development. We aimed to identify miRNAs with the maximum regulatory coverage of previously reported differentially expressed genes in CAKUT tissue compared to controls and bioinformatically characterize a set of these miRNAs which are located in common CNVs. Methods: Differentially expressed genes were identified from ureter tissue transcriptome open data GSE83946 from 15 CAKUT patients and 7 healthy controls, generated in house previously. miRPathDB v2.0 was used for identification of miRNAs with maximum coverage of DEGs(miRNAs which complimentarily regulate all DEGs). Mapping of maximum coverage miRNAs onto common CNVs (frequency >0.2) was performed using UCSC genome browser and gnomAD database. miRNA mapping common CNVs were further bioinformatically analyzed using miRPathDB v2.0. Results: In a maximum coverage set of 50 miRNAs interacting with DEGs in CAKUT, we have identified 3 miRNA geneslocated in the common CNVs(hsa-miR-663b, hsa-miR-3180-3p and hsa-miR-1302). Using Reactome database we identified all three miRNAsto be significantly enriched in the pathway Neuronal System: -log(p-value)>2.326 for hsa-miR-1302; -log(p-value)>1.556 for hsa-miR-3180-3p; and -log(pvalue)>1.703 for hsa-miR-663b. Conclusion: CAKUT is characterized with variable penetrability and expressivity and often followed with other comorbiditiessuch as neurodevelopmental disorders. miRNAsinvolved in DEG networks and prone to CNV effects could present modulating factors of the disease phenotype. Further studies should provide additional evidence about hsa-miR-1302, hsa-miR-3180-3p and hsa-miR-663b involvements in CAKUT etiology",
journal = "CoMBoS2 – the Second Congress of Molecular Biologists of Serbia : Book of abstracts",
title = "Identification of micro RNA from common copy number variants as risk factors for CAKUT",
pages = "62-62",
url = "https://hdl.handle.net/21.15107/rcub_vinar_12465"
}

Životić, I., Mitrović, K., Kolić, I., Seke, M., Živković, M., Stanković, A.,& Jovanović, I.. (2023). Identification of micro RNA from common copy number variants as risk factors for CAKUT. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia : Book of abstracts, 62-62.
https://hdl.handle.net/21.15107/rcub_vinar_12465

Životić I, Mitrović K, Kolić I, Seke M, Živković M, Stanković A, Jovanović I. Identification of micro RNA from common copy number variants as risk factors for CAKUT. in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia : Book of abstracts. 2023;:62-62.
https://hdl.handle.net/21.15107/rcub_vinar_12465 .

Životić, Ivan, Mitrović, Kristina, Kolić, Ivana, Seke, Mariana, Živković, Maja, Stanković, Aleksandra, Jovanović, Ivan, "Identification of micro RNA from common copy number variants as risk factors for CAKUT" in CoMBoS2 – the Second Congress of Molecular Biologists of Serbia : Book of abstracts (2023):62-62,
https://hdl.handle.net/21.15107/rcub_vinar_12465 .

TY  - CONF
AU  - Životić, Ivan
AU  - Kolić, Ivana
AU  - Popić, Kristina
AU  - Filipović Tričković, Jelena G.
AU  - Đorđević, Ana
AU  - Živković, Maja
AU  - Stanković, Aleksandra
AU  - Jovanović, Ivan G.
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10831
AB  - Introduction: Genetic studies of congenital anomalies of the kidney and urinary tract (CAKUT) have demonstrated variable penetrability and expressivity of the associated genetic defects. Previously, it was shown that deletions of 17q12 and 22q11.2 regions were specific for kidney anomalies (KA) while 16p11.2 and 1q21.1 loci showed extensive pleiotropy in CAKUT phenotypes. CNVs affecting miRNA gene dosage have been described to have functional influence on gene expression. We aimed to conduct comprehensive in silico analysis using publicly available databases to analyze miRNA content of CAKUT-associated CNVs in quoted chromosomal loci with regard to pleiotropy.  Methods: Extensive literature review was conducted to collect data about pathogenic rCNVs associated with CAKUT. UCSC genome browser tool was employed for mapping miRNAs onto collected rCNV regions.  Results: Analysis of CNVs in CAKUT included four studies counting more than 2500 patients. In further analysis we included 191 patients harboring pathogenic CNVs. Surprisingly, CAKUT pleiotropic regions (16p11.2, 1q21.2) did not contain any miRNA. 22q11.2 showed the densest miRNAs content (n = 21).  Conclusions: Absence of miRNAs may potentially pronounce the pleiotropy of the CAKUT genetic defects, thus leading to the variety of phenotypes. Contrary, abundancy of miRNAs in 22q11.2 might be associated with reproducible phenotype, such as KA, producing the functional effect when deleted. This assumption agrees with recent results of miRNA expression variability in 22q11.2 deletion syndrome.
C3  - European Journal of Human Genetics
T1  - miRNA-free rare pathogenic CNVs could drive toward variable CAKUT phenotypes
VL  - 30
IS  - Suppl. 1
SP  - 331
UR  - https://hdl.handle.net/21.15107/rcub_vinar_10831
ER  - 

@conference{
author = "Životić, Ivan and Kolić, Ivana and Popić, Kristina and Filipović Tričković, Jelena G. and Đorđević, Ana and Živković, Maja and Stanković, Aleksandra and Jovanović, Ivan G.",
year = "2022",
abstract = "Introduction: Genetic studies of congenital anomalies of the kidney and urinary tract (CAKUT) have demonstrated variable penetrability and expressivity of the associated genetic defects. Previously, it was shown that deletions of 17q12 and 22q11.2 regions were specific for kidney anomalies (KA) while 16p11.2 and 1q21.1 loci showed extensive pleiotropy in CAKUT phenotypes. CNVs affecting miRNA gene dosage have been described to have functional influence on gene expression. We aimed to conduct comprehensive in silico analysis using publicly available databases to analyze miRNA content of CAKUT-associated CNVs in quoted chromosomal loci with regard to pleiotropy.  Methods: Extensive literature review was conducted to collect data about pathogenic rCNVs associated with CAKUT. UCSC genome browser tool was employed for mapping miRNAs onto collected rCNV regions.  Results: Analysis of CNVs in CAKUT included four studies counting more than 2500 patients. In further analysis we included 191 patients harboring pathogenic CNVs. Surprisingly, CAKUT pleiotropic regions (16p11.2, 1q21.2) did not contain any miRNA. 22q11.2 showed the densest miRNAs content (n = 21).  Conclusions: Absence of miRNAs may potentially pronounce the pleiotropy of the CAKUT genetic defects, thus leading to the variety of phenotypes. Contrary, abundancy of miRNAs in 22q11.2 might be associated with reproducible phenotype, such as KA, producing the functional effect when deleted. This assumption agrees with recent results of miRNA expression variability in 22q11.2 deletion syndrome.",
journal = "European Journal of Human Genetics",
title = "miRNA-free rare pathogenic CNVs could drive toward variable CAKUT phenotypes",
volume = "30",
number = "Suppl. 1",
pages = "331",
url = "https://hdl.handle.net/21.15107/rcub_vinar_10831"
}

Životić, I., Kolić, I., Popić, K., Filipović Tričković, J. G., Đorđević, A., Živković, M., Stanković, A.,& Jovanović, I. G.. (2022). miRNA-free rare pathogenic CNVs could drive toward variable CAKUT phenotypes. in European Journal of Human Genetics, 30(Suppl. 1), 331.
https://hdl.handle.net/21.15107/rcub_vinar_10831

Životić I, Kolić I, Popić K, Filipović Tričković JG, Đorđević A, Živković M, Stanković A, Jovanović IG. miRNA-free rare pathogenic CNVs could drive toward variable CAKUT phenotypes. in European Journal of Human Genetics. 2022;30(Suppl. 1):331.
https://hdl.handle.net/21.15107/rcub_vinar_10831 .

Životić, Ivan, Kolić, Ivana, Popić, Kristina, Filipović Tričković, Jelena G., Đorđević, Ana, Živković, Maja, Stanković, Aleksandra, Jovanović, Ivan G., "miRNA-free rare pathogenic CNVs could drive toward variable CAKUT phenotypes" in European Journal of Human Genetics, 30, no. Suppl. 1 (2022):331,
https://hdl.handle.net/21.15107/rcub_vinar_10831 .

TY  - CONF
AU  - Mitrović, Kristina
AU  - Kolić, Ivana
AU  - Životić, Ivan
AU  - Filipović Tričković, Jelena G.
AU  - Đorđević, Ana
AU  - Živković, Maja
AU  - Stanković, Aleksandra
AU  - Jovanović, Ivan G.
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10830
AB  - Introduction: miR-548 family members, located on all human chromosomes except chr19 and chrY, regulate podocyte differentiation in vitro, important for kidney development. Rare copy number variants (rCNVs) are the common genetic cause of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) and could harbour miRNAs. The aim of this study was to investigate to which extent rCNVs associated with CAKUT harbour miR-548 members.
Materials and Methods: Extensive literature review was conducted to collect data of pathogenic and likely pathogenic rCNVs in CAKUT patients. UCSC genome browser tool was employed for mapping of miR-548 members onto collected rCNV regions and gnomAD SV controls database. Bioinformatic analysis was conducted using miRPathDB2 tool.
Results: We generated CAKUT database of pathogenic CNVs in 79 chromosome regions from 191 patient and likely pathogenic CNVs in 74 regions from 87 patients. Pathogenic rCNVs of seventeen patients, located on 7 chromosomes, contained at least one miR-548 member. Likely pathogenic rCNVs of 4 patients, located on 3 chromosomes, contained one of miR-548 members. Bioinformatic analysis implied the role of mapped miRNAs in the regulation of processes associated with CAKUT. In controls, only hsa-mir-548i-3 (out of 73 precursors) was mapped on polymorphic CNVs (af>1%) and wasn’t identified in patients.
Conclusions: miR-548 members located in rCNVs should be investigated in future studies as potential genetic drivers of CAKUT development, beyond protein coding genes.
C3  - European Journal of Human Genetics
T1  - Are miR-548 family members potential genetic drivers of CAKUT
VL  - 30
IS  - Suppl. 1
SP  - 331
UR  - https://hdl.handle.net/21.15107/rcub_vinar_10830
ER  - 

@conference{
author = "Mitrović, Kristina and Kolić, Ivana and Životić, Ivan and Filipović Tričković, Jelena G. and Đorđević, Ana and Živković, Maja and Stanković, Aleksandra and Jovanović, Ivan G.",
year = "2022",
abstract = "Introduction: miR-548 family members, located on all human chromosomes except chr19 and chrY, regulate podocyte differentiation in vitro, important for kidney development. Rare copy number variants (rCNVs) are the common genetic cause of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) and could harbour miRNAs. The aim of this study was to investigate to which extent rCNVs associated with CAKUT harbour miR-548 members.
Materials and Methods: Extensive literature review was conducted to collect data of pathogenic and likely pathogenic rCNVs in CAKUT patients. UCSC genome browser tool was employed for mapping of miR-548 members onto collected rCNV regions and gnomAD SV controls database. Bioinformatic analysis was conducted using miRPathDB2 tool.
Results: We generated CAKUT database of pathogenic CNVs in 79 chromosome regions from 191 patient and likely pathogenic CNVs in 74 regions from 87 patients. Pathogenic rCNVs of seventeen patients, located on 7 chromosomes, contained at least one miR-548 member. Likely pathogenic rCNVs of 4 patients, located on 3 chromosomes, contained one of miR-548 members. Bioinformatic analysis implied the role of mapped miRNAs in the regulation of processes associated with CAKUT. In controls, only hsa-mir-548i-3 (out of 73 precursors) was mapped on polymorphic CNVs (af>1%) and wasn’t identified in patients.
Conclusions: miR-548 members located in rCNVs should be investigated in future studies as potential genetic drivers of CAKUT development, beyond protein coding genes.",
journal = "European Journal of Human Genetics",
title = "Are miR-548 family members potential genetic drivers of CAKUT",
volume = "30",
number = "Suppl. 1",
pages = "331",
url = "https://hdl.handle.net/21.15107/rcub_vinar_10830"
}

Mitrović, K., Kolić, I., Životić, I., Filipović Tričković, J. G., Đorđević, A., Živković, M., Stanković, A.,& Jovanović, I. G.. (2022). Are miR-548 family members potential genetic drivers of CAKUT. in European Journal of Human Genetics, 30(Suppl. 1), 331.
https://hdl.handle.net/21.15107/rcub_vinar_10830

Mitrović K, Kolić I, Životić I, Filipović Tričković JG, Đorđević A, Živković M, Stanković A, Jovanović IG. Are miR-548 family members potential genetic drivers of CAKUT. in European Journal of Human Genetics. 2022;30(Suppl. 1):331.
https://hdl.handle.net/21.15107/rcub_vinar_10830 .

Mitrović, Kristina, Kolić, Ivana, Životić, Ivan, Filipović Tričković, Jelena G., Đorđević, Ana, Živković, Maja, Stanković, Aleksandra, Jovanović, Ivan G., "Are miR-548 family members potential genetic drivers of CAKUT" in European Journal of Human Genetics, 30, no. Suppl. 1 (2022):331,
https://hdl.handle.net/21.15107/rcub_vinar_10830 .

TY  - JOUR
AU  - Mitrović, Kristina
AU  - Životić, Ivan
AU  - Kolić, Ivana
AU  - Đorđević, Ana
AU  - Žakula, Jelena
AU  - Filipović Tričković, Jelena G.
AU  - Živković, Maja
AU  - Stanković, Aleksandra
AU  - Jovanović, Ivan G.
PY  - 2022
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/10469
AB  - Rare copy number variants (CNVs) are among the most common genomic disorders underlying CAKUT. miRNAs located in rare CNVs represent well-founded functional variants for human CAKUT research. The study aimed to identify and functionally interpret miRNAs most frequently affected by rare CNVs in CAKUT and to estimate the overall burden of rare CNVs on miRNA genes in CAKUT. The additional aim of this study was to experimentally confirm the effect of a rare CNV in CAKUT on candidate miRNA’s expression and the subsequent change in mRNA levels of selected target genes. A database of CAKUT-associated rare CNV regions, created by literature mining, was used for mapping of the miRNA precursors. miRNAs and miRNA families, most frequently affected by rare CAKUT-associated CNVs, have been subjected to bioinformatic analysis. CNV burden analysis was performed to identify chromosomes with over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT. A functional study was performed on HEK293 MIR484+/- KO and HEK293 WT cell lines, followed by the analysis of relative miRNA and mRNA target gene levels. 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. An over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT was observed in multiple chromosomes, such as chr16, chr20, and chr21. A significant 0.37 fold downregulation of hsa-miR-484, followed by a notable upregulation of MDM2 and APAF1 and downregulation of NOTCH3 was detected in HEK293 MIR484+/- KO compared to HEK293 WT cell lines, supporting the study hypothesis. miRNA genes are frequently affected by rare CNVs in CAKUT patients. Understanding the potential of CNV-affected miRNAs to participate in CAKUT as genetic drivers represent a crucial implication for the development of novel therapeutic approaches.
T2  - Scientific Reports
T1  - Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT
VL  - 12
IS  - 1
SP  - 17746
DO  - 10.1038/s41598-022-22749-1
ER  - 

@article{
author = "Mitrović, Kristina and Životić, Ivan and Kolić, Ivana and Đorđević, Ana and Žakula, Jelena and Filipović Tričković, Jelena G. and Živković, Maja and Stanković, Aleksandra and Jovanović, Ivan G.",
year = "2022",
abstract = "Rare copy number variants (CNVs) are among the most common genomic disorders underlying CAKUT. miRNAs located in rare CNVs represent well-founded functional variants for human CAKUT research. The study aimed to identify and functionally interpret miRNAs most frequently affected by rare CNVs in CAKUT and to estimate the overall burden of rare CNVs on miRNA genes in CAKUT. The additional aim of this study was to experimentally confirm the effect of a rare CNV in CAKUT on candidate miRNA’s expression and the subsequent change in mRNA levels of selected target genes. A database of CAKUT-associated rare CNV regions, created by literature mining, was used for mapping of the miRNA precursors. miRNAs and miRNA families, most frequently affected by rare CAKUT-associated CNVs, have been subjected to bioinformatic analysis. CNV burden analysis was performed to identify chromosomes with over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT. A functional study was performed on HEK293 MIR484+/- KO and HEK293 WT cell lines, followed by the analysis of relative miRNA and mRNA target gene levels. 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. An over/underrepresentation of miRNA genes in rare CNVs associated with CAKUT was observed in multiple chromosomes, such as chr16, chr20, and chr21. A significant 0.37 fold downregulation of hsa-miR-484, followed by a notable upregulation of MDM2 and APAF1 and downregulation of NOTCH3 was detected in HEK293 MIR484+/- KO compared to HEK293 WT cell lines, supporting the study hypothesis. miRNA genes are frequently affected by rare CNVs in CAKUT patients. Understanding the potential of CNV-affected miRNAs to participate in CAKUT as genetic drivers represent a crucial implication for the development of novel therapeutic approaches.",
journal = "Scientific Reports",
title = "Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT",
volume = "12",
number = "1",
pages = "17746",
doi = "10.1038/s41598-022-22749-1"
}

Mitrović, K., Životić, I., Kolić, I., Đorđević, A., Žakula, J., Filipović Tričković, J. G., Živković, M., Stanković, A.,& Jovanović, I. G.. (2022). Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT. in Scientific Reports, 12(1), 17746.
https://doi.org/10.1038/s41598-022-22749-1

Mitrović K, Životić I, Kolić I, Đorđević A, Žakula J, Filipović Tričković JG, Živković M, Stanković A, Jovanović IG. Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT. in Scientific Reports. 2022;12(1):17746.
doi:10.1038/s41598-022-22749-1 .

Mitrović, Kristina, Životić, Ivan, Kolić, Ivana, Đorđević, Ana, Žakula, Jelena, Filipović Tričković, Jelena G., Živković, Maja, Stanković, Aleksandra, Jovanović, Ivan G., "Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT" in Scientific Reports, 12, no. 1 (2022):17746,
https://doi.org/10.1038/s41598-022-22749-1 . .