Copy-number variation analysis in familial nonsyndromic congenital anomalies of the kidney and urinary tract: Evidence for the causative role of a transposable element-associated genomic rearrangement

Siomou,Ekaterini; Mitsioni,Artemis  G.; Giapros,Vasileios; Bouba,Ioanna; Noutsopoulos,Dimitrios; Georgiou,Ioannis

doi:10.3892/mmr.2017.6462

Copy-number variation analysis in familial nonsyndromic congenital anomalies of the kidney and urinary tract: Evidence for the causative role of a transposable element-associated genomic rearrangement

Authors:
- Ekaterini Siomou
- Artemis G. Mitsioni
- Vasileios Giapros
- Ioanna Bouba
- Dimitrios Noutsopoulos
- Ioannis Georgiou
View Affiliations

Affiliations: Department of Pediatrics, University Hospital of Ioannina, Ioannina 45500, Greece, Laboratory of Medical Genetics and Human Reproduction, Faculty of Medicine, University of Ioannina, Ioannina 45500, Greece, Neonatal Intensive Care Unit, University Hospital of Ioannina, Ioannina 45500, Greece, Laboratory of General Biology, Faculty of Medicine, University of Ioannina, Ioannina 45500, Greece
Published online on: April 12, 2017 https://doi.org/10.3892/mmr.2017.6462
Pages: 3631-3636
Copyright: © Siomou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Most congenital anomalies of the kidney and urinary tract (CAKUT) are sporadic, but familial occurrence has been described, suggesting a genetic contribution. Copy‑number variations (CNVs) were detected in patients with CAKUT to identify possible novel genomic regions associated with CAKUT. CNVs were investigated in 7 children with CAKUT from three unrelated families using array comparative genomic hybridization: female monozygotic twins with bilateral duplex collecting system/vesicoureteral reflux (VUR)/unilateral renal hypodyspasia (URHD); two male siblings with VUR/URHD; 3 male second cousins, one with bilateral VUR/URHD, one with bilateral VUR and one with ureterovesical junction obstruction (UVJO). Five patients had a normal constitution of CNVs, one had a duplication of 0.2 Mb on the 5q‑arm (5q23.3), probably unrelated to CAKUT, and one with UVJO had a 1.4 Mb deletion on the 17q‑arm (17q12) which includes a known CAKUT gene, HNF1B. The phenotype of HNF1B deletion was extended including renal magnesium wasting. A higher coverage in transposable elements (TEs) was found in the deleted region compared with the expected density in any random genomic region. Notably, the 5' breakpoint was mapped within a solo long terminal repeat (LTR) sequence. Moreover, highly similar members of solo LTR and mammalian interspersed repetitive (MIR) elements, as well as nucleotide sequence microhomology were detected at the breakpoint regions. In conclusion, the deletion detected in one patient suggests this genomic imbalance as causative for UVJO. A not very well known phenotype of HNF1B deletion resulting in both low urinary tract malformations and renal wasting of magnesium was described. The high load in TEs of the deleted region, the presence of highly similar elements, and the microhomology found at breakpoint regions may have contributed to the generation of the deletion. CNV analysis could reveal novel causative genomic regions in patients with CAKUT, and further studies in larger cohorts are needed.

View Figures

View References

1	Melo BF, Aguiar MB, Bouzada MC, Aguiar RL, Pereira AK, Paixão GM, Linhares MC, Valerio FC, Simões E Silva AC and Oliveira EA: Early risk factors for neonatal mortality in CAKUT: Analysis of 524 affected newborns. Pediatr Nephrol. 27:965–972. 2012. View Article : Google Scholar : PubMed/NCBI
2	Weber S, Landwehr C, Renkert M, Hoischen A, Wühl E, Denecke J, Radlwimmer B, Haffner D, Schaefer F and Weber RG: Mapping candidate regions and genes for congenital anomalies of the kidneys and urinary tract (CAKUT) by array-based comparative genomic hybridization. Nephrol Dial Transplant. 26:136–143. 2011. View Article : Google Scholar : PubMed/NCBI
3	Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM, Soliman NA, Bogdanovic R, Kehinde EO, et al: Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int. 85:1429–1433. 2014. View Article : Google Scholar : PubMed/NCBI
4	Caruana G, Wong MN, Walker A, Heloury Y, Webb N, Johnstone L, James PA, Burgess T and Bertram JF: Copy-number variation associated with congenital anomalies of the kidney and urinary tract. Pediatr Nephrol. 30:487–495. 2015. View Article : Google Scholar : PubMed/NCBI
5	Hancks DC and Kazazian HH Jr: Active human retrotransposons: Variation and disease. Curr Opin Genet Dev. 22:191–203. 2012. View Article : Google Scholar : PubMed/NCBI
6	Kidd JM, Graves T, Newman TL, Fulton R, Hayden HS, Malig M, Kallicki J, Kaul R, Wilson RK and Eichler EE: A human genome structural variation sequencing resource reveals insights into mutational mechanisms. Cell. 143:837–847. 2010. View Article : Google Scholar : PubMed/NCBI
7	Hancks DC and Kazazian HH Jr: Roles for retrotransposon insertions in human disease. Mob DNA. 7:92016. View Article : Google Scholar : PubMed/NCBI
8	Elisaf M, Panteli K, Theodorou J and Siamopoulos KC: Fractional excretion of magnesium in normal subjects and in patients with hypomagnesemia. Magnes Res. 10:315–320. 1997.PubMed/NCBI
9	Bianchetti MG, Edefonti A and Bettinelli A: The biochemical diagnosis of Gitelman disease and the definition of ‘hypocalciuria’. Pediatr Nephrol. 18:409–411. 2003.PubMed/NCBI
10	Medical versus surgical treatment of primary vesicoureteral reflux: Report of the International Reflux Study Committee. Pediatrics. 67:392–400. 1981.PubMed/NCBI
11	Sanna-Cherchi S, Kiryluk K, Burgess KE, Bodria M, Sampson MG, Hadley D, Nees SN, Verbitsky M, Perry BJ, Sterken R, et al: Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet. 91:987–997. 2012. View Article : Google Scholar : PubMed/NCBI
12	Westland R, Verbitsky M, Vukojevic K, Perry BJ, Fasel DA, Zwijnenburg PJ, Bökenkamp A, Gille JJ, Saraga-Babic M, Ghiggeri GM, et al: Copy number variation analysis identifies novel CAKUT candidate genes in children with a solitary functioning kidney. Kidney Int. 88:1402–1410. 2015. View Article : Google Scholar : PubMed/NCBI
13	Lindner TH, Njolstad PR, Horikawa Y, Bostad L, Bell GI and Sovik O: A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta. Hum Mol Genet. 8:2001–2008. 1999. View Article : Google Scholar : PubMed/NCBI
14	Nakayama M, Nozu K, Goto Y, Kamei K, Ito S, Sato H, Emi M, Nakanishi K, Tsuchiya S and Iijima K: HNF1B alterations associated with congenital anomalies of the kidney and urinary tract. Pediatr Nephrol. 25:1073–1079. 2010. View Article : Google Scholar : PubMed/NCBI
15	Thomas R, Sanna-Cherchi S, Warady BA, Furth SL, Kaskel FJ and Gharavi AG: HNF1B and PAX2 mutations are a common cause of renal hypodysplasia in the CKiD cohort. Pediatr Nephrol. 26:897–903. 2011. View Article : Google Scholar : PubMed/NCBI
16	Coffinier C, Barra J, Babinet C and Yaniv M: Expression of the vHNF1/HNF1beta homeoprotein gene during mouse organogenesis. Mech Dev. 89:211–213. 1999. View Article : Google Scholar : PubMed/NCBI
17	Kolatsi-Joannou M, Bingham C, Ellard S, Bulman MP, Allen LI, Hattersley AT and Woolf AS: Hepatocyte nuclear factor-1beta: A new kindred with renal cysts and diabetes and gene expression in normal human development. J Am Soc Nephrol. 12:2175–2180. 2001.PubMed/NCBI
18	Adalat S, Woolf AS, Johnstone KA, Wirsing A, Harries LW, Long DA, Hennekam RC, Ledermann SE, Rees L, van't Hoff W, et al: HNF1B mutations associate with hypomagnesemia and renal magnesium wasting. J Am Soc Nephrol. 20:1123–1131. 2009. View Article : Google Scholar : PubMed/NCBI
19	Murray PJ, Thomas K, Mulgrew CJ, Ellard S, Edghill EL and Bingham C: Whole gene deletion of the hepatocyte nuclear factor-1beta gene in a patient with the prune-belly syndrome. Nephrol Dial Transplant. 23:2412–2415. 2008. View Article : Google Scholar : PubMed/NCBI
20	Meij IC, Koenderink JB, Van Bokhoven H, Assink KF, Groenestege WT, de Pont JJ, Bindels RJ, Monnens LA, van den Heuvel LP and Knoers NV: Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit. Nat Genet. 26:265–266. 2000. View Article : Google Scholar : PubMed/NCBI
21	Nicolaou N, Renkema KY, Bongers EM, Giles RH and Knoers NV: Genetic, environmental, and epigenetic factors involved in CAKUT. Nat Rev Nephrol. 11:720–731. 2015. View Article : Google Scholar : PubMed/NCBI
22	Schedl A: Renal abnormalities and their developmental origin. Nat Rev Genet. 8:791–802. 2007. View Article : Google Scholar : PubMed/NCBI
23	Friedli M and Trono D: The developmental control of transposable elements and the evolution of higher species. Annu Rev Cell Dev Biol. 31:429–451. 2015. View Article : Google Scholar : PubMed/NCBI
24	Babatz TD and Burns KH: Functional impact of the human mobilome. Curr Opin Genet Dev. 23:264–270. 2013. View Article : Google Scholar : PubMed/NCBI
25	Mandal PK and Kazazian HH Jr: SnapShot: Vertebrate transposons. Cell. 135:192.e12008. View Article : Google Scholar
26	Pearson CE, Edamura K Nichol and Cleary JD: Repeat instability: Mechanisms of dynamic mutations. Nat Rev Genet. 6:729–742. 2005. View Article : Google Scholar : PubMed/NCBI
27	Koumbaris G, Hatzisevastou-Loukidou H, Alexandrou A, Ioannides M, Christodoulou C, Fitzgerald T, Rajan D, Clayton S, Kitsiou-Tzeli S, Vermeesch JR, et al: FoSTeS, MMBIR and NAHR at the human proximal Xp region and the mechanisms of human Xq isochromosome formation. Hum Mol Genet. 20:1925–1936. 2011. View Article : Google Scholar : PubMed/NCBI