Original Report: Patient-Oriented, Translational Research
Identification of 8 Novel Mutations in Nephrogenesis-Related Genes in Chinese Han Patients with Unilateral Renal AgenesisWu H.a · Xu Q.a · Xie J.a · Ma J.a · Qiao P.a · Zhang W.a · Yu H.a · Wang W.a · Qian Y.a · Zhang Q.a · Guo Y.a · Tang Y.b · Chen X.a · Wang Z.a · Chen N.a
aDepartment of Nephrology, Institute of Nephrology, and bDepartment of Radiology, Shanghai Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Do you have an account?
- Rent for 48h to view
- Buy Cloud Access for unlimited viewing via different devices
- Synchronizing in the ReadCube Cloud
- Printing and saving restrictions apply
Rental: USD 8.50
Cloud: USD 20.00
Article / Publication Details
Background: Few genetic studies have focused on unilateral renal agenesis (URA), which is a disorder with insidious clinical manifestations and a tendency to result in renal failure. We aimed to detect pathogenic mutations in nephrogenesis-related genes, which were identified by a literature review conducted among a large cohort of Chinese Han patients with URA. Methods: Totally, 86 unrelated URA patients were included. All URA patients were diagnosed by employing radiological methods. Patients with a solitary kidney owing to nephrectomy or renal atrophy due to secondary factors were excluded. Nine (10.5%) patients had a family history of abnormal nephrogenesis. Fifteen (17.4%) had other malformations in the urogenital system. All coding exons and adjacent intron regions of 25 genes were analyzed using next-generation sequencing and validated by Sanger sequencing and 100 ethnically matched healthy controls. Results: Ten conserved mutations (9 missense mutations and 1 deletion mutation) were identified in SALL1, EYA1, RET, HNF1B, DSTYK, WNT4, and SIX5. All mutations were novel or rare (frequency <0.1%) in the public databases and absent from the 100 healthy controls. Nine patients carried mutations in candidate genes. Most of the patients carried one single heterozygous mutation, except for 2, who respectively carried compound heterozygous mutations and 2 single heterozygous mutations. In addition, 2 patients shared the same mutation in DSTYK. Conclusion: A total of 10.5% of our URA cases could be explained by mutations in our candidate genes. The mutations in nephrogenesis-related genes in the Chinese Han patients with URA had a decentralized distribution without any hotspot mutations.
© 2017 S. Karger AG, Basel
- Westland R, Schreuder MF, Ket JC, van Wijk JA: Unilateral renal agenesis: a systematic review on associated anomalies and renal injury. Nephrol Dial Transplant 2013;28:1844-1855.
- Schedl A: Renal abnormalities and their developmental origin. Nat Rev Genet 2007;8:791-802.
- Argueso LR, Ritchey ML, Boyle ET Jr, Milliner DS, Bergstralh EJ, Kramer SA: Prognosis of patients with unilateral renal agenesis. Pediatr Nephrol 1992;6:412-416.
- Westland R, Kurvers RA, van Wijk JA, Schreuder MF: Risk factors for renal injury in children with a solitary functioning kidney. Pediatrics 2013;131:e478-e485.
- Colquhoun-Kerr JS, Gu WX, Jameson JL, Withers S, Bode HH: X-linked Kallmann syndrome and renal agenesis occurring together and independently in a large Australian family. Am J Med Genet 1999;83:23-27.
- Zenteno JC, Mendez JP, Maya-Nunez G, Ulloa-Aguirre A, Kofman-Alfaro S: Renal abnormalities in patients with Kallmann syndrome. BJU Int 1999;83:383-386.
- Chatterjee R, Ramos E, Hoffman M, VanWinkle J, Martin DR, Davis TK, Hoshi M, Hmiel SP, Beck A, Hruska K, Coplen D, Liapis H, Mitra R, Druley T, Austin P, Jain S: Traditional and targeted exome sequencing reveals common, rare and novel functional deleterious variants in RET-signaling complex in a cohort of living US patients with urinary tract malformations. Hum Genet 2012;131:1725-1738.
- Skinner MA, Safford SD, Reeves JG, Jackson ME, Freemerman AJ: Renal aplasia in humans is associated with RET mutations. Am J Hum Genet 2008;82:344-351.
- Heidet L, Decramer S, Pawtowski A, Moriniere V, Bandin F, Knebelmann B, Lebre AS, Faguer S, Guigonis V, Antignac C, Salomon R: Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol 2010;5:1079-1090.
- Hwang DY, Dworschak GC, Kohl S, Saisawat P, Vivante A, Hilger AC, Reutter HM, Soliman NA, Bogdanovic R, Kehinde EO, Tasic V, Hildebrandt F: Mutations in 12 known dominant disease-causing genes clarify many congenital anomalies of the kidney and urinary tract. Kidney Int 2014;85:1429-1433.
- Hoskins BE, Cramer CH, Silvius D, Zou D, Raymond RM, Orten DJ, Kimberling WJ, Smith RJ, Weil D, Petit C, Otto EA, Xu PX, Hildebrandt F: Transcription factor SIX5 is mutated in patients with branchio-oto-renal syndrome. Am J Hum Genet 2007;80:800-804.
- Weber S, Taylor JC, Winyard P, Baker KF, Sullivan-Brown J, Schild R, Knuppel T, Zurowska AM, Caldas-Alfonso A, Litwin M, Emre S, Ghiggeri GM, Bakkaloglu A, Mehls O, Antignac C, Network E, Schaefer F, Burdine RD: SIX2 and BMP4 mutations associate with anomalous kidney development. J Am Soc Nephrol 2008;19:891-903.
- Kohl S, Hwang DY, Dworschak GC, Hilger AC, Saisawat P, Vivante A, Stajic N, Bogdanovic R, Reutter HM, Kehinde EO, Tasic V, Hildebrandt F: Mild recessive mutations in six Fraser syndrome-related genes cause isolated congenital anomalies of the kidney and urinary tract. J Am Soc Nephrol 2014;25:1917-1922.
- Saisawat P, Tasic V, Vega-Warner V, Kehinde EO, Gunther B, Airik R, Innis JW, Hoskins BE, Hoefele J, Otto EA, Hildebrandt F: Identification of two novel CAKUT-causing genes by massively parallel exon resequencing of candidate genes in patients with unilateral renal agenesis. Kidney Int 2012;81:196-200.
- Vandrovcova J, Thomas ER, Atanur SS, Norsworthy PJ, Neuwirth C, Tan Y, Kasperaviciute D, Biggs J, Game L, Mueller M, Soutar AK, Aitman TJ: The use of next-generation sequencing in clinical diagnosis of familial hypercholesterolemia. Genet Med 2013;15:948-957.
- Moriniere V, Dahan K, Hilbert P, Lison M, Lebbah S, Topa A, Bole-Feysot C, Pruvost S, Nitschke P, Plaisier E, Knebelmann B, Macher MA, Noel LH, Gubler MC, Antignac C, Heidet L: Improving mutation screening in familial hematuric nephropathies through next generation sequencing. J Am Soc Nephrol 2014;25:2740-2751.
- Vivante A, Mark-Danieli M, Davidovits M, Harari-Steinberg O, Omer D, Gnatek Y, Cleper R, Landau D, Kovalski Y, Weissman I, Eisenstein I, Soudack M, Wolf HR, Issler N, Lotan D, Anikster Y, Dekel B: Renal hypodysplasia associates with a WNT4 variant that causes aberrant canonical WNT signaling. J Am Soc Nephrol 2013;24:550-558.
- Weber S, Moriniere V, Knuppel T, Charbit M, Dusek J, Ghiggeri GM, Jankauskiene A, Mir S, Montini G, Peco-Antic A, Wuhl E, Zurowska AM, Mehls O, Antignac C, Schaefer F, Salomon R: Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol 2006;17:2864-2870.
- Sajithlal G, Zou D, Silvius D, Xu PX: Eya 1 acts as a critical regulator for specifying the metanephric mesenchyme. Dev Biol 2005;284:323-336.
- Xu PX, Adams J, Peters H, Brown MC, Heaney S, Maas R: Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia. Nat Genet 1999;23:113-117.
- Kobayashi H, Kawakami K, Asashima M, Nishinakamura R: Six1 and Six4 are essential for Gdnf expression in the metanephric mesenchyme and ureteric bud formation, while Six1 deficiency alone causes mesonephric-tubule defects. Mech Dev 2007;124:290-303.
- Brodbeck S, Englert C: Genetic determination of nephrogenesis: the Pax/Eya/Six gene network. Pediatr Nephrol 2004;19:249-255.
- Sanna-Cherchi S, Sampogna RV, Papeta N, Burgess KE, Nees SN, Perry BJ, Choi M, Bodria M, Liu Y, Weng PL, Lozanovski VJ, Verbitsky M, Lugani F, Sterken R, Paragas N, Caridi G, Carrea A, Dagnino M, Materna-Kiryluk A, Santamaria G, Murtas C, Ristoska-Bojkovska N, Izzi C, Kacak N, Bianco B, Giberti S, Gigante M, Piaggio G, Gesualdo L, Kosuljandic Vukic D, Vukojevic K, Saraga-Babic M, Saraga M, Gucev Z, Allegri L, Latos-Bielenska A, Casu D, State M, Scolari F, Ravazzolo R, Kiryluk K, Al-Awqati Q, D'Agati VD, Drummond IA, Tasic V, Lifton RP, Ghiggeri GM, Gharavi AG: Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 2013;369:621-629.
- Pitera JE, Woolf AS, Basson MA, Scambler PJ: Sprouty1 haploinsufficiency prevents renal agenesis in a model of Fraser syndrome. J Am Soc Nephrol 2012;23:1790-1796.
- Stark K, Vainio S, Vassileva G, McMahon AP: Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 1994;372:679-683.
- Halt K, Vainio S: Coordination of kidney organogenesis by Wnt signaling. Pediatr Nephrol 2014;29:737-744.
- Clissold RL, Hamilton AJ, Hattersley AT, Ellard S, Bingham C: HNF1B-associated renal and extra-renal disease - an expanding clinical spectrum. Nat Rev Nephrol 2015;11:102-112.
- Lokmane L, Heliot C, Garcia-Villalba P, Fabre M, Cereghini S: vHNF1 functions in distinct regulatory circuits to control ureteric bud branching and early nephrogenesis. Development 2010;137:347-357.
- Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP: Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell 2005;9:283-292.
Sanchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M: Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 1996;382:70-73.
- Jeanpierre C, Mace G, Parisot M, Moriniere V, Pawtowsky A, Benabou M, Martinovic J, Amiel J, Attie-Bitach T, Delezoide AL, Loget P, Blanchet P, Gaillard D, Gonzales M, Carpentier W, Nitschke P, Tores F, Heidet L, Antignac C, Salomon R; Societe Francaise de Foetopathologie: RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects. J Med Genet 2011;48:497-504.
- Nicolaou N, Pulit SL, Nijman IJ, Monroe GR, Feitz WF, Schreuder MF, van Eerde AM, de Jong TP, Giltay JC, van der Zwaag B, Havenith MR, Zwakenberg S, van der Zanden LF, Poelmans G, Cornelissen EA, Lilien MR, Franke B, Roeleveld N, van Rooij IA, Cuppen E, Bongers EM, Giles RH, Knoers NV, Renkema KY: Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT. Kidney Int 2016;89:476-486.
- Kircher M, Witten DM, Jain P, O'Roak BJ, Cooper GM, Shendure J: A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 2014;46:310-315.
- Quang D, Chen Y, Xie X: DANN: a deep learning approach for annotating the pathogenicity of genetic variants. Bioinformatics 2015;31:761-763.
- Dong C, Wei P, Jian X, Gibbs R, Boerwinkle E, Wang K, Liu X: Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum Mol Genet 2015;24:2125-2137.
- Ionita-Laza I, McCallum K, Xu B, Buxbaum JD: A spectral approach integrating functional genomic annotations for coding and noncoding variants. Nat Genet 2016;48:214-220.
- Ioannidis NM, Rothstein JH, Pejaver V, Middha S, McDonnell SK, Baheti S, Musolf A, Li Q, Holzinger E, Karyadi D, Cannon-Albright LA, Teerlink CC, Stanford JL, Isaacs WB, Xu J, Cooney KA, Lange EM, Schleutker J, Carpten JD, Powell IJ, Cussenot O, Cancel-Tassin G, Giles GG, MacInnis RJ, Maier C, Hsieh CL, Wiklund F, Catalona WJ, Foulkes WD, Mandal D, Eeles RA, Kote-Jarai Z, Bustamante CD, Schaid DJ, Hastie T, Ostrander EA, Bailey-Wilson JE, Radivojac P, Thibodeau SN, Whittemore AS, Sieh W: REVEL: an ensemble method for predicting the pathogenicity of rare missense variants. Am J Hum Genet 2016;99:877-885.
- 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: Copy-number disorders are a common cause of congenital kidney malformations. Am J Hum Genet 2012;91:987-997.
- Hwang DY, Kohl S, Fan X, Vivante A, Chan S, Dworschak GC, Schulz J, van Eerde AM, Hilger AC, Gee HY, Pennimpede T, Herrmann BG, van de Hoek G, Renkema KY, Schell C, Huber TB, Reutter HM, Soliman NA, Stajic N, Bogdanovic R, Kehinde EO, Lifton RP, Tasic V, Lu W, Hildebrandt F: Mutations of the SLIT2-ROBO2 pathway genes SLIT2 and SRGAP1 confer risk for congenital anomalies of the kidney and urinary tract. Hum Genet 2015;134:905-916.
- Kosfeld A, Kreuzer M, Daniel C, Brand F, Schafer AK, Chadt A, Weiss AC, Riehmer V, Jeanpierre C, Klintschar M, Brasen JH, Amann K, Pape L, Kispert A, Al-Hasani H, Haffner D, Weber RG: Whole-exome sequencing identifies mutations of TBC1D1 encoding a Rab-GTPase-activating protein in patients with congenital anomalies of the kidneys and urinary tract (CAKUT). Hum Genet 2016;135:69-87.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.