Doğumsal Böbrek ve İdrar Yolları Anomalilerinde MicroRNA Gen Polimorfizmleri

Amaç: Doğuştan böbrek ve üriner traktus anomalilerinin (CAKUT) patogenezi bilinmemektedir. Etiyolojide güçlü bir genetik yatkınlık vardır. Bu çalışmada CAKUT’da mikroRNA sentez yolağında görevli gen polimorfizmlerinin rolü araştırıldı. Materyal ve Metod: Mersin Üniversitesi Tıp Fakültesi Çocuk Nefrolojisi Polikliniği’nde izlenen CAKUT tanılı 147 hasta [Ureteropelvik bileşke darlığı: (n: 39), vezicoureteral reflü (VUR) (n: 37), renal parankimal malformasyonlar (n:43), böbreğin embriyonik migrasyon anomalileri (n: 28)] ve 51 sağlıklı çocuk çalışmaya dahil edildi. RNASEN, DGCR8, XPO5, RAN, DICER1, GEMIN3 gen polimorfizmleri Mersin Üniversitesi Tıp Fakültesi Tıbbi Biyoloji Anabilim Dalı’nda çalışıldı. Bulgular: Hasta ve kontrol grubu arasında gen polimorfizmleri karşılaştırıldığında istatistiksel olarak anlamlı bir fark bulunmadı. GEMIN3 geni mutant allel sıklığı VUR grubunda renal parankimal malformasyon grubuna oranla daha yüksek saptandı. Sonuç: CAKUT’da miRNA oluşum yolağında görevli gen polimorfizmlerinin patogenezi açıklayabilmesi için daha fazla sayıda hasta içeren çalışmalara ihtiyaç vardır. GEMIN3 geni mutant allelleri CAKUT spektrumu içinde VUR ile ilişkili olabilir

MicroRNA Gene Polymorphisms in Congenital Anomalies of the Kidney and Urinary Tract

Purpose: Pathogenesis of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT) is unknown. A strong genetic contribution is emphasized. In this study we investigated the role of microRNA gene polymorphism in CAKUT. Material and Methods: 147 patients with CAKUT [(Ureteropelvic junction obstruction n: 39, vesicoureteral reflux (VUR) (n: 37), renal parenchymal malformations (n:43), anomalies of renal embryonic migration (n: 28)] and 51 healthy children were enrolled in the study. RNASEN, DGCR8, XPO5, RAN, DICER1, GEMIN3 gene polymorphisms were studied. Results: When the patient and control group were compared by polymorphisms no statistically significant difference was found. But GEMIN3 mutant allel frequency was significantly higher in VUR group than renal parenchymal malformation group. Conclusions: Mutant alleles of the GEMIN3 gene might be related to VUR pathogenesis within the context of the CAKUT spectrum. But studies with larger number of patients are required to delineate the association between CAKUT pathogenesis and microRNA gene polymorphisms.

___

  • Loane M, Dolk H, Kelly A, Teljeur C, Greenlees R, Densem J; EUROCAT Working Group. Paper 4: EUROCAT statistical monitoring: identification and investigation of ten years trend of congenital anomalies in Europe. Birth Defects Res A Clin Mol Teratol. 2011;91:31-43.
  • Sanna-Cherchi S, Ravani P, Corbani V, Parodi S, Haupt R, Piaggio G, Innocenti ML, Somenzi D, Trivelli A, Caridi G,et al. Renal outcome in patients with congenital anomalies of the kidney and urinary tract. Kidney Int. 2009;76:528-33.
  • Mansoor O, Chandar J, Rodriguez MM Abitbol CL, Seeherunvong W, Freundlich M, Zilleruelo G. Long term risk of chronic kidney disease in unilateral multicystic dysplastic kidney. Pediatr Nephrol. 2011;26:597-603.
  • Yosypiv IV. Congenital anomalies of the kidney and urinary tract: a genetic disorder? Int J Nephrol. 2012;90:9083-93.
  • Uetani N, Bouchard M. Plumbing in the embryo: developmental defects of the urinary tracts. Clin Genet. 2009;75:307-17.
  • Rumballe B, Georgas K, Wilkinson L, Little M. Molecular anatomy of the kidney: what have we learned from gene expression and functional genomics? Pediatr Nephrol. 2010;25:1005-16.
  • Ambros V. The functions of animal microRNAs. Nature. 2004;431:350-5.
  • Bartel DP. MicroRNAs: genomics, biogenesis, mechanism and function. Cell. 2004;116:281-97. 9. Schedl A. Renal abnormalities and their developmental origin. Nat Rev Genet. 2007;8:791- 802.
  • Woolf AS. A molecular and genetic view of human renal and urinary tract malformations. Kidney Int. 2000;58:500-12.
  • Vainio S, Lin Y. Coordinating early kidney development: lessons from gene targeting. Nat Rev Genet. 2002;3:533-43.
  • Sanna-Cherchi S, Caridi G, Weng PL, Scolari F, Perfumo F, Gharavi AG, Ghiggeri GM. Genetic approaches to human renal agenesis/hypoplasia and dysplasia. Pediatr Nephrol. 2007;22:1675-84.
  • Ho J, Pandey P, Schatton P, Sims-Lucas S, Khalid M, Frank MH, Hartwig S, Kreidberg JA. The pro- apoptotic protein BIM is a microRNA target in kidney progenitor. J Am Soc Nephrol. 2011;22:1053-62.
  • Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. Human RISC couples microRNA biogenesis and posttranscriptional 2005;123:631-40. silencing. Cell.
  • Miller SA,Dykes DD, Polesky HI. A Simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res.1988;16:12-5.
  • Wilker EH, Baccarelli A, Suh H et al. Black caorbon exposures, blood pressure and interactions with SNP in microRNA processing genes. Environ Health Perspect. 2010;118:943-8.
  • Gascon E, Gao FB. Cause or effect: misregulation of microRNA pathways in neurodegeneration. Front Neurosci. 2012;6:48.
  • Boni V, Zarate R, Villa JC, Bandrés E, Gomez MA, Maiello E, Garcia-Foncillas J, Aranda E. Role of primary miRNA polymorphic variants in metastatic colon cancer patients treated with 5-FLU and irinotecan. Pharmacogenomics J 2011;11:429-36.
  • Ryan BM, Robles AL, Harris CC. Genetic variation in microRNA networks: the implications for cancer research. Nat Rev Cancer. 2010;10:389-402.
  • Horikawa Y, Wood CG, Yang H. SNP of microRNA machinery genes modify the risk of renal cell carcinoma. Clin Cancer Res. 2008;14:7956-62.
  • Marrone AK, Ho J. MicroRNAs: potential regulators of renal development genes that contribute to CAKUT. Pediatr Nephrol 2014;29:565–74.
  • Mouillet JF, Yan X, Ou Q, Jin L, Muglia LJ, Crawford PA, Sadovsky Y. DEAD-Box Protein-103 is essantial for early embriyonic development and modulates ovarian morphology and function. Endocrinology. 2008;149:2168-75.
  • Harvey SJ, Jarad G, Cunningham J, Goldberg S, Schermer B, Harfe BD, McManus MT, Benzing T, Miner JH. Podocyte spesific deletion of dicer alters cytoskeletal Dynamics and causes glomerular disease. J Am Soc Nephrol 2008;19:2150-8.
  • Ho J, Ng KH, Rosen S, Dostal A,Gregory RI, Kreidberg JA. Podocyte spesific loss of functional microRNAs leads to rapid glomerular and tubuler injury. J Am Soc Nephrol. 2008;19:2069-75.
  • Nagalakshmi VK, Ren Q, Pugh MM, Valerius MT, McMahon AP, Yu J. Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. Kidney Int. 2011;79:317-30.
  • Sequeira Lopez ML, Weatherford ET, Borges GR, Monteagudo MC, Pentz ES, Harfe BD, Carretero O, Sigmund CD, Gomez RA. The microRNA processing enzyme dicer maintains juxtaglomerular cells. J Am Soc Nephrol. 2010;21: 460-7.
  • Shi S, Yu L, Chiu C, Sun Y, Chen J, Khitrov G, Merkenschlager M, Holzman LB, Zhang W, Mundel P, et al. Podocyte selective deletion of dicer induces proteinuria and glomerulosclerosis. J Am Soc Nephrol. 2008;19:2159-69.
  • Wei Q, Bhatt K, He HZ, Mi QS, Haase VH, Dong Z. Targeted deletion of Dicer from proximal tubules protects against renal ischemia-reperfusion injury. J Am Soc Nephrol. 2010;21:756-61.
  • Pastorelli LM, Wells S, Fray M, Smith A, Hough T, Harfe BD, McManus MT, Smith L, Woolf AS, Cheeseman M, et al. Genetic analyses reveal a requirement for Dicer1 in the Mouse urogenital tract. Mamm Genome. 2009;20:140-51.
  • Zhdanova O, Srivastava S, Di L, Li Z, Tchelebi L, Dworkin S, Johnstone DB, Zavadil J, Chong MM, Littman DR,et al. The inducible deletion of Drosha and microRNAs in mature podocytes results in a collapsing glomerulopathy. Kidney Int. 2011;80:719- 30.
  • Vivante A, Kohl S, Hwang DW, Dworschak GC, Hildebrant F. Single-gene causes of congenital anomalies of the kidnet and urinary tract (CAKUT) in humans. Pediatr Nephrol. 2014;29:695-704.
Cukurova Medical Journal-Cover
  • ISSN: 2602-3032
  • Yayın Aralığı: Yılda 4 Sayı
  • Başlangıç: 1976
  • Yayıncı: Çukurova Üniversitesi Tıp Fakültesi