Top

24-04-2024 | Vesicorenal Reflux | Original Article

Copy number variation analysis identifies MIR9-3 and MIR1299 as novel miRNA candidate genes for CAKUT

Authors: Ivan Zivotic, Ivana Kolic, Mirjana Cvetkovic, Brankica Spasojevic-Dimitrijeva, Maja Zivkovic, Aleksandra Stankovic, Ivan Jovanovic

Published in: Pediatric Nephrology

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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.

Graphical abstract

Available only for authorised users

Lanzoni M, Morris J, Garne E, Loane M, Kinsner-Ovaskainen A (2017) European monitoring of congenital anomalies: JRC-EUROCAT Report on Statistical Monitoring of Congenital Anomalies (2006 – 2015). https://doi.org/10.2760/157556

Harambat J, van Stralen KJ, Kim JJ, Tizard EJ (2012) Epidemiology of chronic kidney disease in children. Pediatr Nephrol 27:363–373. https://doi.org/10.1007/s00467-011-1939-1CrossRefPubMed

Sanna-Cherchi S, Westland R, Ghiggeri GM, Gharavi AG (2018) Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest 128:4–15. https://doi.org/10.1172/JCI95300CrossRefPubMedPubMedCentral

Verbitsky M, Westland R, Perez A, Kiryluk K, Liu Q, Krithivasan P, Mitrotti A, Fasel DA, Batourina E, Sampson MG, Bodria M, Werth M, Kao C, Martino J, Capone VP, Vivante A, Shril S, Kil BH, Marasà M, Zhang JY, Na YJ, Lim TY, Ahram D, Weng PL, Heinzen EL, Carrea A, Piaggio G, Gesualdo L, Manca V, Masnata G, Gigante M, Cusi D, Izzi C, Scolari F, van Wijk JAE, Saraga M, Santoro D, Conti G, Zamboli P, White H, Drozdz D, Zachwieja K, Miklaszewska M, Tkaczyk M, Tomczyk D, Krakowska A, Sikora P, Jarmoliński T, Borszewska-Kornacka MK, Pawluch R, Szczepanska M, Adamczyk P, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Dobson MG, Darlow JM, Puri P, Barton DE, Furth SL, Warady BA, Gucev Z, Lozanovski VJ, Tasic V, Pisani I, Allegri L, Rodas LM, Campistol JM, Jeanpierre C, Alam S, Casale P, Wong CS, Lin F, Miranda DM, Oliveira EA, Simões-E-Silva AC, Barasch JM, Levy B, Wu N, Hildebrandt F, Ghiggeri GM, Latos-Bielenska A, Materna-Kiryluk A, Zhang F, Hakonarson H, Papaioannou VE, Mendelsohn CL, Gharavi AG, Sanna-Cherchi S (2019) The copy number variation landscape of congenital anomalies of the kidney and urinary tract. Nat Genet 51:117–127. https://doi.org/10.1038/s41588-018-0281-yCrossRefPubMed

Mitrovic K, Zivotic I, Kolic I, Djordjevic A, Zakula J, Filipovic Trickovic J, Zivkovic M, Stankovic A, Jovanovic I (2022) Identification and functional interpretation of miRNAs affected by rare CNVs in CAKUT. Sci Rep 12:17746. https://doi.org/10.1038/s41598-022-22749-1CrossRefPubMedPubMedCentral

Marcinkowska M, Szymanski M, Krzyzosiak WJ, Kozlowski P (2011) Copy number variation of microRNA genes in the human genome. BMC Genomics 12:183. https://doi.org/10.1186/1471-2164-12-183CrossRefPubMedPubMedCentral

Wu X, Zhang D, Li G (2012) Insights into the regulation of human CNV-miRNAs from the view of their target genes. BMC Genomics 13:707. https://doi.org/10.1186/1471-2164-13-707CrossRefPubMedPubMedCentral

Kajbafzadeh AM, Payabvash S, Salmasi AH, Monajemzadeh M, Tavangar SM (2006) Smooth muscle cell apoptosis and defective neural development in congenital ureteropelvic junction obstruction. J Urol 176:718–723. https://doi.org/10.1016/j.juro.2006.03.041CrossRefPubMed

Davis TK, Hoshi M, Jain S (2014) To bud or not to bud: the RET perspective in CAKUT. Pediatr Nephrol 29:597–608. https://doi.org/10.1007/s00467-013-2606-5CrossRefPubMedPubMedCentral

10.

Stankovic A (2021) Promising biomarkers in pediatric chronic kidney disease through the kaleidoscope of CAKUT background complexity. Pediatr Nephrol 36:1321–1325. https://doi.org/10.1007/s00467-020-04877-wCrossRefPubMed

11.

Cui Y, Lyu X, Ding L, Ke L, Yang D, Pirouz M, Qi Y, Ong J, Gao G, Du P, Gregory RI (2021) Global miRNA dosage control of embryonic germ layer specification. Nature 593:602–606. https://doi.org/10.1038/s41586-021-03524-0CrossRefPubMedPubMedCentral

12.

Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317. https://doi.org/10.1016/j.cell.2007.03.030CrossRefPubMed

13.

Venkatesan N, Deepa PR, Khetan V, Krishnakumar S (2015) Computational and in vitro investigation of miRNA-gene regulations in retinoblastoma pathogenesis: miRNA mimics strategy. Bioinform Biol Insights 9:89–101. https://doi.org/10.4137/BBI.S21742CrossRefPubMedPubMedCentral

14.

Van Neste C, Laird A, O’Mahony F, Van Criekinge W, Deforce D, Van Nieuwerburgh F, Powles T, Harrison DJ, Stewart GD, De Meyer T (2017) Epigenetic sampling effects: nephrectomy modifies the clear cell renal cell cancer methylome. Cell Oncol 40:293–297. https://doi.org/10.1007/s13402-016-0313-5CrossRef

15.

Schiavinato JLDS, Haddad R, Saldanha-Araujo F, Baiochi J, Araujo AG, Santos Scheucher P, Covas DT, Zago MA, Panepucci RA (2017) TGF-beta/atRA-induced Tregs express a selected set of microRNAs involved in the repression of transcripts related to Th17 differentiation. Sci Rep 7:3627. https://doi.org/10.1038/s41598-017-03456-8CrossRefPubMedPubMedCentral

16.

Cao S, Li L, Li J, Zhao H (2020) MiR-1299 Impedes the progression of non-small-cell lung cancer through EGFR/PI3K/AKT signaling pathway. Onco Targets Ther 13:7493–7502. https://doi.org/10.2147/OTT.S250396CrossRefPubMedPubMedCentral

17.

He S, Wang G, Ni J, Zhuang J, Zhuang S, Wang G, Ye Y, Xia W (2018) MicroRNA-511 inhibits cellular proliferation and invasion in colorectal cancer by directly targeting hepatoma-derived growth factor. Oncol Res 26:1355–1363. https://doi.org/10.3727/096504018X15154094331876CrossRefPubMedPubMedCentral

18.

Maheu M, Lopez JP, Crapper L, Davoli MA, Turecki G, Mechawar N (2015) MicroRNA regulation of central glial cell line-derived neurotrophic factor (GDNF) signalling in depression. Transl Psychiatry 5:e511. https://doi.org/10.1038/tp.2015.11CrossRefPubMedPubMedCentral

19.

Hou S, Ye Z, Liao D, Bai L, Liu Y, Zhang J, Kijlstra A, Yang P (2016) miR-23a, miR-146a and miR-301a confer predisposition to Vogt-Koyanagi-Harada syndrome but not to Behcet’s disease. Sci Rep 6:20057. https://doi.org/10.1038/srep20057CrossRefPubMedPubMedCentral

20.

Yang L, Du L, Yue Y, Huang Y, Zhou Q, Cao S, Qi J, Liang L, Wu L, Wang C, Ye Z, Tian Y, Kijlstra A, Hou S, Yang P (2017) miRNA copy number variants confer susceptibility to acute anterior uveitis with or without ankylosing spondylitis. Invest Ophthalmol Vis Sci 58:1991–2001. https://doi.org/10.1167/iovs.16-21047CrossRefPubMed

21.

Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, Nees SN, Verbitsky M, Perry BJ, Sterken R, Lozanovski VJ, Materna-Kiryluk A, Barlassina C, Kini A, Corbani V, Carrea A, Somenzi D, Murtas C, Ristoska-Bojkovska N, Izzi C, Bianco B, Zaniew M, Flogelova H, Weng PL, Kacak N, Giberti S, Gigante M, Arapovic A, Drnasin K, Caridi G, Curioni S, Allegri F, Ammenti A, Ferretti S, Goj V, Bernardo L, Jobanputra V, Chung WK, Lifton RP, Sanders S, State M, Clark LN, Saraga M, Padmanabhan S, Dominiczak AF, Foroud T, Gesualdo L, Gucev Z, Allegri L, Latos-Bielenska A, Cusi D, Scolari F, Tasic V, Hakonarson H, Ghiggeri GM, Gharavi AG (2012) Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet 91:987–997. https://doi.org/10.1016/j.ajhg.2012.10.007CrossRefPubMedPubMedCentral

22.

Westland R, Verbitsky M, Vukojevic K, Perry BJ, Fasel DA, Zwijnenburg PJ, Bökenkamp A, Gille JJ, Saraga-Babic M, Ghiggeri GM, D’Agati VD, Schreuder MF, Gharavi AG, van Wijk JA, Sanna-Cherchi S (2015) Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney Int 88:1402–1410. https://doi.org/10.1038/ki.2015.239CrossRefPubMedPubMedCentral

23.

Shi X, Yang H, Chen C, Hou J, Ji T, Cheng J, Birchler JA (2022) Effect of aneuploidy of a non-essential chromosome on gene expression in maize. Plant J 110:193–211. https://doi.org/10.1111/tpj.15665CrossRefPubMedPubMedCentral

24.

Zhu Y, Zhou P, Tong J, Luo Y, Jiang W (2021) Influence of miR-9 on inflammatory factors and VEGF expression in acute kidney injury. Int J Clin Exp Med 14:1884–1891. https://e-century.us/files/ijcem/14/5/ijcem0116325.pdf. Accessed Aug 2023

25.

Fierro-Fernández M, Miguel V, Márquez-Expósito L, Nuevo-Tapioles C, Herrero JI, Blanco-Ruiz E, Tituaña J, Castillo C, Cannata P, Monsalve M, Ruiz-Ortega M, Ramos R, Lamas S (2020) MiR-9-5p protects from kidney fibrosis by metabolic reprogramming. FASEB J 34:410–431. https://doi.org/10.1096/fj.201901599RRCrossRefPubMed

26.

Li D, Sun L (2020) MicroRNAs and polycystic kidney disease. Kidney Med 2:762–770. https://doi.org/10.1016/j.xkme.2020.06.013CrossRefPubMedPubMedCentral

27.

Zhang J, Jia J, Zhao L, Li X, Xie Q, Chen X, Wang J, Lu F (2016) Down-regulation of microRNA-9 leads to activation of IL-6/Jak/STAT3 pathway through directly targeting IL-6 in HeLa cell. Mol Carcinog 55:732–742. https://doi.org/10.1002/mc.22317CrossRefPubMed

28.

Apostolou A, Poreau B, Delrieu L, Thévenon J, Jouk PS, Lallemand G, Emadali A, Sartelet H (2020) High activation of the AKT pathway in human multicystic renal dysplasia. Pathobiology 87:302–310. https://doi.org/10.1159/000509152CrossRefPubMed

29.

Lantinga-van Leeuwen IS, Leonhard WN, van der Wal A, Breuning MH, de Heer E, Peters DJ (2007) Kidney-specific inactivation of the Pkd1 gene induces rapid cyst formation in developing kidneys and a slow onset of disease in adult mice. Hum Mol Genet 16:3188–3196. https://doi.org/10.1093/hmg/ddm299CrossRefPubMed

30.

Leonhard WN, Zandbergen M, Veraar K, van den Berg S, van der Weerd L, Breuning M, de Heer E, Peters DJ (2015) Scattered deletion of PKD1 in kidneys causes a cystic snowball effect and recapitulates polycystic kidney disease. J Am Soc Nephrol 26:1322–1333. https://doi.org/10.1681/ASN.2013080864CrossRefPubMed

31.

Pritchard L, Sloane-Stanley JA, Sharpe JA, Aspinwall R, Lu W, Buckle V, Strmecki L, Walker D, Ward CJ, Alpers CE, Zhou J, Wood WG, Harris PC (2000) A human PKD1 transgene generates functional polycystin-1 in mice and is associated with a cystic phenotype. Hum Mol Genet 9:2617–2627. https://doi.org/10.1093/hmg/9.18.2617CrossRefPubMed

32.

Thivierge C, Kurbegovic A, Couillard M, Guillaume R, Coté O, Trudel M (2006) Overexpression of PKD1 causes polycystic kidney disease. Mol Cell Biol 26:1538–1548. https://doi.org/10.1128/MCB.26.4.1538-1548.2006CrossRefPubMedPubMedCentral

33.

Kaiyuan D, Lijuan H, Xueyuan S, Yunhui Z (2021) The role and underlying mechanism of miR-1299 in cancer. Future Sci OA 7:FSO693. https://doi.org/10.2144/fsoa-2021-0014

34.

Pei Y, Li K, Lou X, Wu Y, Dong X, Wang W, Li N, Zhang D, Cui W (2020) miR-1299/NOTCH3/TUG1 feedback loop contributes to the malignant proliferation of ovarian cancer. Oncol Rep 44:438–448. https://doi.org/10.3892/or.2020.7623CrossRefPubMedPubMedCentral

35.

Sang M, Meng L, Liu S, Ding P, Chang S, Ju Y, Liu F, Gu L, Lian Y, Geng C (2018) Circular RNA ciRS-7 maintains metastatic phenotypes as a ceRNA of miR-1299 to target MMPs. Mol Cancer Res 16:1665–1675. https://doi.org/10.1158/1541-7786.MCR-18-0284CrossRefPubMed

36.

Zhang L, Sun D, Zhang J, Tian Y (2021) Circ-UBR1 facilitates proliferation, metastasis, and inhibits apoptosis in breast cancer by regulating the miR-1299/CCND1 axis. Life Sci 266:118829. https://doi.org/10.1016/j.lfs.2020.118829CrossRefPubMed

37.

Wilkinson LJ, Neal CS, Singh RR, Sparrow DB, Kurniawan ND, Ju A, Grieve SM, Dunwoodie SL, Moritz KM, Little MH (2015) Renal developmental defects resulting from in utero hypoxia are associated with suppression of ureteric β-catenin signaling. Kidney Int 87:975–983. https://doi.org/10.1038/ki.2014.394CrossRefPubMed

38.

Romashkova JA, Makarov SS (1999) NF-κB is a target of AKT in anti-apoptotic PDGF signalling. Nature 401:86–90. https://doi.org/10.1038/43474CrossRefPubMed

39.

Zhang H, Sun SC (2015) NF-κB in inflammation and renal diseases. Cell Biosci 5:63. https://doi.org/10.1186/s13578-015-0056-4CrossRefPubMedPubMedCentral

40.

Knoers NVAM (2022) The term CAKUT has outlived its usefulness: the case for the defense. Pediatr Nephrol 37:2793–2798. https://doi.org/10.1007/s00467-022-05678-zCrossRefPubMedPubMedCentral

41.

Verbitsky M, Krithivasan P, Batourina E, Khan A, Graham SE, Marasà M, Kim H, Lim TY, Weng PL, Sánchez-Rodríguez E, Mitrotti A, Ahram DF, Zanoni F, Fasel DA, Westland R, Sampson MG, Zhang JY, Bodria M, Kil BH, Shril S, Gesualdo L, Torri F, Scolari F, Izzi C, van Wijk JAE, Saraga M, Santoro D, Conti G, Barton DE, Dobson MG, Puri P, Furth SL, Warady BA, Pisani I, Fiaccadori E, Allegri L, Degl’Innocenti ML, Piaggio G, Alam S, Gigante M, Zaza G, Esposito P, Lin F, Simões-E-Silva AC, Brodkiewicz A, Drozdz D, Zachwieja K, Miklaszewska M, Szczepanska M, Adamczyk P, Tkaczyk M, Tomczyk D, Sikora P, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Lozanovski VJ, Gucev Z, Ionita-Laza I, Stanaway IB, Crosslin DR, Wong CS, Hildebrandt F, Barasch J, Kenny EE, Loos RJF, Levy B, Ghiggeri GM, Hakonarson H, Latos-Bieleńska A, Materna-Kiryluk A, Darlow JM, Tasic V, Willer C, Kiryluk K, Sanna-Cherchi S, Mendelsohn CL, Gharavi AG (2021) Copy number variant analysis and genome-wide association study identify loci with large effect for vesicoureteral reflux. J Am Soc Nephrol 32:805–820. https://doi.org/10.1681/ASN.2020050681CrossRefPubMedPubMedCentral

42.

Acuna-Hidalgo R, Sengul H, Steehouwer M, van de Vorst M, Vermeulen SH, Kiemeney LALM, Veltman JA, Gilissen C, Hoischen A (2017) Ultra-sensitive sequencing identifies high prevalence of clonal hematopoiesis-associated mutations throughout adult life. Am J Hum Genet 101:50–64. https://doi.org/10.1016/j.ajhg.2017.05.013CrossRefPubMedPubMedCentral

43.

Voet T, Kumar P, Van Loo P, Cooke SL, Marshall J, Lin ML, Zamani Esteki M, Van der Aa N, Mateiu L, McBride DJ, Bignell GR, McLaren S, Teague J, Butler A, Raine K, Stebbings LA, Quail MA, D’Hooghe T, Moreau Y, Futreal PA, Stratton MR, Vermeesch JR, Campbell PJ (2013) Single-cell paired-end genome sequencing reveals structural variation per cell cycle. Nucleic Acids Res 41:6119–6138. https://doi.org/10.1093/nar/gkt345CrossRefPubMedPubMedCentral

44.

Chu JH, Rogers A, Ionita-Laza I, Darvishi K, Mills RE, Lee C, Raby BA (2013) Copy number variation genotyping using family information. BMC Bioinformatics 14:157. https://doi.org/10.1186/1471-2105-14-157CrossRefPubMedPubMedCentral

45.

Wu CW, Lim TY, Wang C, Seltzsam S, Zheng B, Schierbaum L, Schneider S, Mann N, Connaughton DM, Nakayama M, van der Ven AT, Dai R, Kolvenbach CM, Kause F, Ottlewski I, Stajic N, Soliman NA, Kari JA, El Desoky S, Fathy HM, Milosevic D, Turudic D, Al Saffar M, Awad HS, Eid LA, Ramanathan A, Senguttuvan P, Mane SM, Lee RS, Bauer SB, Lu W, Hilger AC, Tasic V, Shril S, Sanna-Cherchi S, Hildebrandt F (2022) Copy number variation analysis facilitates identification of genetic causation in patients with congenital anomalies of the kidney and urinary tract. Eur Urol Open Sci 44:106–112. https://doi.org/10.1016/j.euros.2022.08.004CrossRefPubMedPubMedCentral

46.

Jovanovic I, Zivkovic M, Kostic M, Krstic Z, Djuric T, Kolic I, Alavantic D, Stankovic A (2016) Transcriptome-wide based identification of miRs in congenital anomalies of the kidney and urinary tract (CAKUT) in children: the significant upregulation of tissue MIR144 expression. J Transl Med 14:193. https://doi.org/10.1186/s12967-016-0955-0CrossRefPubMedPubMedCentral

47.

Zhang F, Gu W, Hurles ME, Lupski JR (2009) Copy number variation in human health, disease, and evolution. Annu Rev Genomics Hum Genet 10:451–481. https://doi.org/10.1146/annurev.genom.9.081307.164217CrossRefPubMedPubMedCentral

Title: Copy number variation analysis identifies MIR9-3 and MIR1299 as novel miRNA candidate genes for CAKUT
Authors: Ivan Zivotic
Ivana Kolic
Mirjana Cvetkovic
Brankica Spasojevic-Dimitrijeva
Maja Zivkovic
Aleksandra Stankovic
Ivan Jovanovic
Publication date: 24-04-2024
Publisher: Springer Berlin Heidelberg
Keywords: Vesicorenal Reflux
Ureteropelvic Junction Obstruction
Published in: Pediatric Nephrology
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-024-06381-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Copy number variation analysis identifies MIR9-3 and MIR1299 as novel miRNA candidate genes for CAKUT

Abstract

Background

Methods

Results

Conclusions

Graphical abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Graphical abstract

Please log in to get access to this content