Novel mutations of PKD genes in the Czech population with autosomal dominant polycystic kidney disease

BMC Medical Genetics

Milada Kohoutova³  Frantisek Losan¹  Vladimir Tesar²  Miroslav Merta³  Jana Reiterova²  Jitka Stekrova³  Veronika Elisakova³  Lena Obeidova³ 

[1] Genetika Plzeň, s.r.o., Parková 1254/11a, 326 00 Plzeň-Černice, Czech Republic;Department of Nephrology of the First Faculty of Medicine and General University Hospital, U Nemocnice 2, 128 08 Prague, Czech Republic;Institute of Biology and Medical Genetics of the First Faculty of Medicine and General University Hospital, Albertov 4, 128 00 Prague, Czech Republic

关键词: Polycystic kidney disease;    MLPA;    HRM;    Mutation;    Mutational analysis;    PKD gene;    ADPKD;   

Others  :  1092158
DOI  :  10.1186/1471-2350-15-41

 received in 2013-08-13, accepted in 2014-03-10,  发布年份 2014

【 摘 要 】

Background

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disorder caused by mutation in either one of two genes, PKD1 and PKD2. High structural and sequence complexity of PKD genes makes the mutational diagnostics of ADPKD challenging. The present study is the first detailed analysis of both PKD genes in a cohort of Czech patients with ADPKD using High Resolution Melting analysis (HRM) and Multiplex Ligation-dependent Probe Amplification (MLPA).

Methods

The mutational analysis of PKD genes was performed in a set of 56 unrelated patients. For mutational screening of the PKD1 gene, the long-range PCR (LR-PCR) strategy followed by nested PCR was used. Resulting PCR fragments were analyzed by HRM; the positive cases were reanalyzed and confirmed by direct sequencing. Negative samples were further examined for sequence changes in the PKD2 gene by the method of HRM and for large rearrangements of both PKD1 and PKD2 genes by MLPA.

Results

Screening of the PKD1 gene revealed 36 different likely pathogenic germline sequence changes in 37 unrelated families/individuals. Twenty-five of these sequence changes were described for the first time. Moreover, a novel large deletion was found within the PKD1 gene in one patient. Via the mutational analysis of the PKD2 gene, two additional likely pathogenic mutations were detected.

Conclusions

Probable pathogenic mutation was detected in 71% of screened patients. Determination of PKD mutations and their type and localization within corresponding genes could help to assess clinical prognosis of ADPKD patients and has major benefit for prenatal and/or presymptomatic or preimplantational diagnostics in affected families as well.

【 授权许可】

   
2014 Obeidova et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 1993, 329:332-342.
• [2]European Polycystic Kidney Disease Consortium: The polycystic kidney disease I gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell 1994, 77:881-894.
• [3]Kimberling WJ, Kumar S, Gabow PA, Kenyon JB, Connolly CJ, Somlo S: Autosomal dominant polycystic kidney disease: localization of the second gene to chromosome 4q13-q23. Genomics 1993, 18:467-472.
• [4]Tan YC, Blumenfeld J, Rennert H: Autosomal dominant polycystic kidney disease: genetics, mutations and microRNAs. Biochim Biophys Acta 1812, 2011:1202-1212.
• [5]Hateboer N, van Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, Torra R, Breuning M, Ravine D: Comparison of phenotypes of polycystic kidney disease types 1 and 2: European PKD1-PKD2 study group. Lancet 1999, 353:103-107.
• [6]Cornec-Le Gall E, Audrézet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, Charasse C, Whebe B, Renaudineau E, Jousset P, Guillodo MP, Grall-Jezequel A, Saliou P, Férec C, Le Meur Y: Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 2013, 24:1006-1013.
• [7]Daoust MC, Reynolds DM, Bichet DG, Somlo S: Evidence for a third genetic locus for autosomal dominant polycystic kidney disease. Genomics 1995, 25:733-736.
• [8]Paul BM, Consugar MB, Ryan Lee M, Sundsbak JL, Heyer CM, Rossetti S, Kubly VJ, Hopp K, Torres VE, Coto E, Clementi M, Bogdanova N, de Almeida E, Bichet DG, Harris PC: Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families. Kidney Int 2013, 85:383-392.
• [9]Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingberg DE, Zhou J: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003, 33:129-137.
• [10]Torres VE, Harris PC: Autosomal dominant polycystic kidney disease: the last 3 years. Kidney Int 2009, 76:149-168.
• [11]Rossetti S, Burton S, Strmecki L, Pond GR, San Millán JL, Zerres K, Barratt TM, Ozen S, Torres VE, Bergstralh EJ, Winearls CG, Harris PC: The position of the polycystic kidney disease 1 (PKD1) gene mutation correlates with the severity of renal disease. J Am Soc Nephrol 2002, 13:1230-1237.
• [12]Rossetti S, Consugar MB, Chapman AB, Torres VE, Guay-Woodford LM, Grantham JJ, Bennett WM, Meyers CM, Walker DL, Bae K, Zhang QJ, Thompson PA, Miller JP, Harris PC, CRISP Consortium: Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 2007, 18:2143-2160.
• [13]Gout AM, Martin NC, Brown AF, Ravine D: PKDB: polycystic kidney disease mutation database–a gene variant database for autosomal dominant polycystic kidney disease. Hum Mutat 2007, 28:654-659.
• [14]Bogdanova N, Markoff A, Gerke V, McCluskey M, Horst J, Dworniczak B: Homologues to the first gene for autosomal dominant polycystic kidney disease are pseudogenes. Genomics 2001, 74:333-341.
• [15]Rossetti S, Kubly VJ, Consugar MB, Hopp K, Roy S, Horsley SW, Chauveau D, Rees L, Barratt TM, van’t Hoff WG, Niaudet P, Torres VE, Harris PC: Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int 2009, 75:848-855.
• [16]Reiterová J, Štekrová J, Merta M, Kotlas J, Elišáková V, Lněnička P, Korabečná M, Kohoutová M, Tesař V: Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele. BMC Nephrol 2013, 14:59. BioMed Central Full Text
• [17]Bergmann C, van Bothmer J, Ortiz Brüchle N, Venghaus A, Frank V, Fehrenbach H, Hampel T, Pape L, Buske A, Jonsson J, Sarioglu N, Santos A, Ferreira JC, Becker JU, Cremer R, Hoefele J, Benz MR, Weber LT, Buettner R, Zerres K: Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J Am Soc Nephrol 2011, 22:2047-2056.
• [18]Consugar MB, Wong WC, Lundquist PA, Rossetti S, Kubly VJ, Walker DL, Rangel LJ, Aspinwall R, Niaudet WP, Ozen S, David A, Velinov M, Bergstralh EJ, Bae KT, Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Sampson JR, Dawson BD, Harris PC, CRISP Consortium: Characterization of large rearrangements in autosomal dominant polycystic kidney disease and the PKD1/TSC2 contiguous gene syndrome. Kidney Int 2008, 74:1468-1479.
• [19]Connor A, Lunt PW, Dolling C, Patel Y, Meredith AL, Gardner A, Hamilton NK, Dudley CR: Mosaicism in autosomal dominant polycystic kidney disease revealed by genetic testing to enable living related renal transplantation. Am J Transplant 2008, 8:232-237.
• [20]Chapman AB, Guay-Woodford LM, Grantham JJ, Torres VE, Bae KT, Baumgarten DA, Kenney PJ, King BF Jr, Glockner JF, Wetzel LH, Brummer ME, O’Neill WC, Robbin ML, Bennett WM, Klahr S, Hirschman GH, Kimmel PL, Thompson PA, Miller JP, Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease cohort: Renal structure in early autosomal-dominant polycystic kidney disease (ADPKD): the consortium for radiologic imaging studies of polycystic kidney disease (CRISP) cohort. Kidney Int 2003, 64:1035-1045.
• [21]Pei Y: Diagnostic approach in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 2006, 1:1108-1114.
• [22]Harris PC, Rossetti S: Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol 2010, 6:197-206.
• [23]Bataille S, Berland Y, Fontes M, Burtey S: High resolution melt analysis for mutation screening in PKD1 and PKD2. BMC Nephrol 2011, 12:57. BioMed Central Full Text
• [24]Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly VJ, Eckloff BW, Ward CJ, Winearls CG, Torres VE, Harris PC: Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol 2012, 23:915-933.
• [25]Qi XP, Du ZF, Ma JM, Chen XL, Zhang Q, Fei J, Wei XM, Chen D, Ke HP, Liu XZ, Li F, Chen ZG, Su Z, Jin HY, Liu WT, Zhao Y, Jiang HL, Lan ZZ, Li PF, Fang MY, Dong W, Zhang XN: Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations. Gene 2013, 516:93-100.
• [26]Pei Y, Obaji J, Dupuis A, Paterson AD, Magistroni R, Dicks E, Parfrey P, Cramer B, Coto E, Torra R, San Millan JL, Gibson R, Breuning M, Peters D, Ravine D: Unified criteria for ultrasonographic diagnosis of ADPKD. J Am Soc Nephrol 2009, 20:205-212.
• [27]Watnick TJ, Piontek KB, Cordal TM, Weber H, Gandolph MA, Qian F, Lens XM, Neumann HP, Germino GG: An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection. Hum Mol Genet 1997, 6:1473-1481.
• [28]Tan YC, Blumenfeld JD, Anghel R, Donahue S, Belenkaya R, Balina M, Parker T, Levine D, Leonard DG, Rennert H: Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat 2009, 30:264-273.
• [29]Chateigner-Boutin AL, Small I: A rapid high-throughput method for the detection and quantification of RNA editing based on high-resolution melting of amplicons. Nucleic Acids Res 2007, 35:e114.
• [30]Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G: Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002, 30:e57.
• [31]Ramensky V, Bork P, Sunyaev S: Human non-synonymous SNPs: server and survey. Nucleic Acids Res 2002, 30:3894-3900.
• [32]Thusberg J, Olatubosun A, Vihinen M: Performance of mutation pathogenicity prediction methods on missense variants. Hum Mutat 2011, 32:358-368.
• [33]Ng PC, Henikoff S: Accounting for human polymorphisms predicted to affect protein function. Genome Res 2002, 12:436-446.
• [34]Brunak S, Engelbrecht J, Knudsen S: Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 1991, 220:49-65.
• [35]Desmet FO, Hamroun D, Lalande M, Collod-Béroud G, Claustres M, Béroud C: Human splicing finder: an online bioinformatics tool to predict splicing signals. Nucleic Acids Res 2009, 37:e67.
• [36]Audrézet MP, Cornec-Le Gall E, Chen JM, Redon S, Quéré I, Creff J, Bénech C, Maestri S, Le Meur Y, Férec C: Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat 2012, 33:1239-1250.
• [37]Rossetti S, Strmecki L, Gamble V, Burton S, Sneddon V, Peral B, Roy S, Bakkaloglu A, Komel R, Winearls CG, Harris PC: Mutation analysis of the entire PKD1 gene: genetic and diagnostic implications. Am J Hum Genet 2001, 68:46-63.
• [38]Inoue S, Inoue K, Utsunomiya M, Nozaki J, Yamada Y, Iwasa T, Mori E, Yoshinaga T, Koizumi A: Mutation analysis in PKD1 of Japanese autosomal dominant polycystic kidney disease patients. Hum Mutat 2002, 19:622-628.
• [39]Yu C, Yang Y, Zou L, Hu Z, Li J, Liu Y, Ma Y, Ma M, Su D, Zhang S: Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease. BMC Med Genet 2011, 12:164. BioMed Central Full Text
• [40]Zhang S, Mei C, Zhang D, Dai B, Tang B, Sun T, Zhao H, Zhou Y, Li L, Wu Y, Wang W, Shen X, Song J: Mutation analysis of autosomal dominant polycystic kidney disease genes in Han Chinese. Nephron Exp Nephrol 2005, 100:e63-e76.
• [41]Turco AE, Rossetti S, Bresin E, Corrà S, Restagno G, Carbonara A, De Prisco O, Gammaro L, Maschio G, Pignatti PF: Detection of two different nonsense mutations in exon 44 of the PKD1 gene in two unrelated Italian families with severe autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 1996, 11:10-12.
• [42]Reiterová J, Stekrová J, Peters DJ, Kapras J, Kohoutová M, Merta M, Zidovská J: Four novel mutations of the PKD2 gene in Czech families with autosomal dominant polycystic kidney disease. Hum Mutat 2002, 19:573.
• [43]Chung W, Kim H, Hwang YH, Kim SY, Ko AR, Ro H, Lee KB, Lee JS, Oh KH, Ahn C: PKD2 gene mutation analysis in Korean autosomal dominant polycystic kidney disease patients using two-dimensional gene scanning. Clin Genet 2006, 70:502-508.
• [44]Chen JM, Cooper DN, Férec C, Kehrer-Sawatzki H, Patrinos GP: Genomic rearrangements in inherited disease and cancer. Semin Cancer Biol 2010, 20:222-233.
• [45]Cooper DN, Bacolla A, Férec C, Vasquez KM, Kehrer-Sawatzki H, Chen JM: On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat 2011, 32:1075-1099.
• [46]Neumann HPH, Bacher J, Nabulsi Z, Ortiz Brüchle N, Hoffmann MM, Schaeffner E, Nürnberger J, Cybulla M, Wilpert J, Riegler P, Corradini R, Kraemer-Guth A, Azurmendi P, Nunez M, Gläsker S, Zerres K, Jilg C: Adult patients with sporadic polycystic kidney disease: the importance of screening for mutations in the PKD1 and PKD2 genes. Int Urol Nephrol 2012, 44:1753-1762.
• [47]Torra R, Badenas C, Darnell A, Nicolau C, Volpini V, Revert L, Estivill X: Linkage, clinical features, and prognosis of autosomal dominant polycystic kidney disease types 1 and 2. J Am Soc Nephrol 1996, 7:2142-2151.
• [48]Hateboer N, Veldhuisen B, Peters D, Breuning MH, San Millán JL, Bogdanova N, Coto E, van Dijk MA, Afzal AR, Jeffery S, Saggar-Malik AK, Torra R, Dimitrakov D, Martinez I, de Castro SS, Krawczak M, Ravine D: Location of mutations within the PKD2 gene influences clinical outcome. Kidney Int 2000, 57:1444-1451.
• [49]Garcia-Gonzalez MA, Jones JG, Allen SK, Palatucci CM, Batish SD, Seltzer WK, Lan Z, Allen E, Qian F, Lens XM, Pei Y, Germino GG, Watnick TJ: Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab 2007, 92:160-167.
• [50]Hoefele J, Mayer K, Scholz M, Klein HG: Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant 2011, 26:2181-2188.
• [51]Tan YC, Michaeel A, Blumenfeld J, Donahue S, Parker T, Levine D, Rennert H: A novel long-range PCR sequencing method for genetic analysis of the entire PKD1 gene. J Mol Diagn 2012, 14:305-313.