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Identification of an NPHP1 deletion causing adult form of nephronophthisis

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Abstract

Aims

Nephronophthisis (NPHP) is an autosomal recessive cystic disease of the kidney with main characteristic features of polyuria/polydipsia, mild or absent proteinuria, interstitial fibrosis, and tubular cysts. NPHP is responsible for 5–10 % of inheritable end-stage renal disease (ESRD) cases. We investigated the clinical features and genetic cause of NPHP in a Persian family with three siblings affected by tubulointerstitial nephropathy reaching ESRD in adulthood.

Methods

Uromodulin (UMOD), known to be involved in adult medullary cystic kidney disease, and nephronophthisis 1 (NPHP1) were investigated in the genomic DNA of the probands using DNA sequencing, multiplex ligation-dependent probe amplification (MLPA) analysis and molecular karyotyping.

Results

No mutation was detected in UMOD. Copy number variation analysis of the NPHP1 gene using the commercially available MLPA kit identified a recurrent large homozygous deletion encompassing all NPHP1 exons. The parents were heterozygous for this deletion. Whole genome array-CGH analysis confirmed a homozygous deletion on chromosome 2q13, NPHP1 site, and revealed that the size of the copy number loss was approximately 102 Kbp.

Conclusion

This is the first report of determination of an NPHP1 deletion size using routine diagnostic methods. The results of this study expand the knowledge about the genotype–phenotype correlations in NPHP1, and have implications for genetic counseling and family planning advice for other affected families. This is the first molecular analysis of NPHP1 in an Iranian kindred.

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References

  1. Waldherr R, Lennert T, Weber HP, Fodisch HJ, Scharer K (1982) The nephronophthisis complex. A clinicopathologic study in children. Virchows Arch A Pathol Anat Histol 394(3):235–254

    Article  CAS  PubMed  Google Scholar 

  2. Hildebrandt F, Zhou W (2007) Nephronophthisis-associated ciliopathies. J Am Soc Nephrol 18(6):1855–1871. doi:10.1681/ASN.2006121344

    Article  CAS  PubMed  Google Scholar 

  3. Ala-Mello S, Sankila EM, Koskimies O, de la Chapelle A, Kaariainen H (1998) Molecular studies in Finnish patients with familial juvenile nephronophthisis exclude a founder effect and support a common mutation causing mechanism. J Med Genet 35(4):279–283

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Blowey DL, Querfeld U, Geary D, Warady BA, Alon U (1996) Ultrasound findings in juvenile nephronophthisis. Pediatr Nephrol 10(1):22–24

    Article  CAS  PubMed  Google Scholar 

  5. Wolf MT, Hildebrandt F (2011) Nephronophthisis. Pediatr Nephrol 26(2):181–194. doi:10.1007/s00467-010-1585-z

    Article  PubMed  Google Scholar 

  6. Hildebrandt F, Strahm B, Nothwang HG, Gretz N, Schnieders B, Singh-Sawhney I, Kutt R, Vollmer M, Brandis M (1997) Molecular genetic identification of families with juvenile nephronophthisis type 1: rate of progression to renal failure. APN Study Group. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Kidney Int 51(1):261–269

    Article  CAS  PubMed  Google Scholar 

  7. Omran H, Fernandez C, Jung M, Haffner K, Fargier B, Villaquiran A, Waldherr R, Gretz N, Brandis M, Ruschendorf F, Reis A, Hildebrandt F (2000) Identification of a new gene locus for adolescent nephronophthisis, on chromosome 3q22 in a large Venezuelan pedigree. Am J Hum Genet 66(1):118–127. doi:10.1086/302705

    Article  CAS  PubMed  Google Scholar 

  8. Krishnan R, Eley L, Sayer JA (2008) Urinary concentration defects and mechanisms underlying nephronophthisis. Kidney Blood Press Res 31(3):152–162. doi:10.1159/000129648

    Article  CAS  PubMed  Google Scholar 

  9. Zollinger HU, Mihatsch MJ, Edefonti A, Gaboardi F, Imbasciati E, Lennert T (1980) Nephronophthisis (medullary cystic disease of the kidney). A study using electron microscopy, immunofluorescence, and a review of the morphological findings. Helv Paediatr Acta 35(6):509–530

    CAS  PubMed  Google Scholar 

  10. Scolari F, Caridi G, Rampoldi L, Tardanico R, Izzi C, Pirulli D, Amoroso A, Casari G, Ghiggeri GM (2004) Uromodulin storage diseases: clinical aspects and mechanisms. Am J Kidney Dis 44(6):987–999

    Article  CAS  PubMed  Google Scholar 

  11. Christodoulou K, Tsingis M, Stavrou C, Eleftheriou A, Papapavlou P, Patsalis PC, Ioannou P, Pierides A, Constantinou Deltas C (1998) Chromosome 1 localization of a gene for autosomal dominant medullary cystic kidney disease. Hum Mol Genet 7(5):905–911

    Article  CAS  PubMed  Google Scholar 

  12. Scolari F, Puzzer D, Amoroso A, Caridi G, Ghiggeri GM, Maiorca R, Aridon P, De Fusco M, Ballabio A, Casari G (1999) Identification of a new locus for medullary cystic disease, on chromosome 16p12. Am J Hum Genet 64(6):1655–1660. doi:10.1086/302414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kirby A, Gnirke A, Jaffe DB, Baresova V, Pochet N, Blumenstiel B, Ye C, Aird D, Stevens C, Robinson JT, Cabili MN, Gat-Viks I, Kelliher E, Daza R, DeFelice M, Hulkova H, Sovova J, Vylet’al P, Antignac C, Guttman M, Handsaker RE, Perrin D, Steelman S, Sigurdsson S, Scheinman SJ, Sougnez C, Cibulskis K, Parkin M, Green T, Rossin E, Zody MC, Xavier RJ, Pollak MR, Alper SL, Lindblad-Toh K, Gabriel S, Hart PS, Regev A, Nusbaum C, Kmoch S, Bleyer AJ, Lander ES, Daly MJ (2013) Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet 45(3):299–303. doi:10.1038/ng.2543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Rampoldi L, Caridi G, Santon D, Boaretto F, Bernascone I, Lamorte G, Tardanico R, Dagnino M, Colussi G, Scolari F, Ghiggeri GM, Amoroso A, Casari G (2003) Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 12(24):3369–3384. doi:10.1093/hmg/ddg353

    Article  CAS  PubMed  Google Scholar 

  15. Hart TC, Gorry MC, Hart PS, Woodard AS, Shihabi Z, Sandhu J, Shirts B, Xu L, Zhu H, Barmada MM, Bleyer AJ (2002) Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet 39(12):882–892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bollee G, Fakhouri F, Karras A, Noel LH, Salomon R, Servais A, Lesavre P, Moriniere V, Antignac C, Hummel A (2006) Nephronophthisis related to homozygous NPHP1 gene deletion as a cause of chronic renal failure in adults. Nephrol Dial Transplant 21(9):2660–2663. doi:10.1093/ndt/gfl348

    Article  PubMed  Google Scholar 

  17. Hoefele J, Nayir A, Chaki M, Imm A, Allen SJ, Otto EA, Hildebrandt F (2011) Pseudodominant inheritance of nephronophthisis caused by a homozygous NPHP1 deletion. Pediatr Nephrol 26(6):967–971. doi:10.1007/s00467-011-1761-9

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chaari I, Trabelsi M, Goucha R, Elaribi Y, Kharrat M, Guarguah T, Maazoul F, Chaabouni H, M’Rad R (2012) Prevalence and incidence estimation of large NPHP1 homozygous deletion in Tunisian population. Pathol Biol. doi:10.1016/j.patbio.2012.05.003

    PubMed  Google Scholar 

  19. Hildebrandt F, Attanasio M, Otto E (2009) Nephronophthisis: disease mechanisms of a ciliopathy. J Am Soc Nephrol 20(1):23–35. doi:10.1681/ASN.2008050456

    Article  CAS  PubMed  Google Scholar 

  20. Soliman NA, Hildebrandt F, Allen SJ, Otto EA, Nabhan MM, Badr AM (2010) Homozygous NPHP1 deletions in Egyptian children with nephronophthisis including an infantile onset patient. Pediatr Nephrol 25(10):2193–2194. doi:10.1007/s00467-010-1539-5

    Article  PubMed  PubMed Central  Google Scholar 

  21. Jiang ST, Chiou YY, Wang E, Lin HK, Lee SP, Lu HY, Wang CK, Tang MJ, Li H (2008) Targeted disruption of Nphp1 causes male infertility due to defects in the later steps of sperm morphogenesis in mice. Hum Mol Genet 17(21):3368–3379. doi:10.1093/hmg/ddn231

    Article  CAS  PubMed  Google Scholar 

  22. van Gravesande KS, Omran H (2005) Primary ciliary dyskinesia: clinical presentation, diagnosis and genetics. Ann Med 37(6):439–449. doi:10.1080/07853890510011985

    Article  Google Scholar 

  23. Torra R, Sarquella J, Calabia J, Marti J, Ars E, Fernandez-Llama P, Ballarin J (2008) Prevalence of cysts in seminal tract and abnormal semen parameters in patients with autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol 3(3):790–793. doi:10.2215/CJN.05311107

    Article  PubMed  PubMed Central  Google Scholar 

  24. Alazami AM, Alshammari MJ, Baig M, Salih MA, Hassan HH, Alkuraya FS (2014) NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male infertility. Clin Genet 85(4):371–375. doi:10.1111/cge.12160

    Article  CAS  PubMed  Google Scholar 

  25. Parisi MA, Bennett CL, Eckert ML, Dobyns WB, Gleeson JG, Shaw DW, McDonald R, Eddy A, Chance PF, Glass IA (2004) The NPHP1 gene deletion associated with juvenile nephronophthisis is present in a subset of individuals with Joubert syndrome. Am J Hum Genet 75(1):82–91. doi:10.1086/421846

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Tory K, Lacoste T, Burglen L, Moriniere V, Boddaert N, Macher MA, Llanas B, Nivet H, Bensman A, Niaudet P, Antignac C, Salomon R, Saunier S (2007) High NPHP1 and NPHP6 mutation rate in patients with Joubert syndrome and nephronophthisis: potential epistatic effect of NPHP6 and AHI1 mutations in patients with NPHP1 mutations. J Am Soc Nephrol 18(5):1566–1575. doi:10.1681/ASN.2006101164

    Article  CAS  PubMed  Google Scholar 

  27. Cooper GM, Coe BP, Girirajan S, Rosenfeld JA, Vu TH, Baker C, Williams C, Stalker H, Hamid R, Hannig V, Abdel-Hamid H, Bader P, McCracken E, Niyazov D, Leppig K, Thiese H, Hummel M, Alexander N, Gorski J, Kussmann J, Shashi V, Johnson K, Rehder C, Ballif BC, Shaffer LG, Eichler EE (2011) A copy number variation morbidity map of developmental delay. Nat Genet 43(9):838–846. doi:10.1038/ng.909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Riggs ER, Church DM, Hanson K, Horner VL, Kaminsky EB, Kuhn RM, Wain KE, Williams ES, Aradhya S, Kearney HM, Ledbetter DH, South ST, Thorland EC, Martin CL (2012) Towards an evidence-based process for the clinical interpretation of copy number variation. Clin Genet 81(5):403–412. doi:10.1111/j.1399-0004.2011.01818.x

    Article  CAS  PubMed  Google Scholar 

  29. Halbritter J, Porath JD, Diaz KA, Braun DA, Kohl S, Chaki M, Allen SJ, Soliman NA, Hildebrandt F, Otto EA (2013) Identification of 99 novel mutations in a worldwide cohort of 1,056 patients with a nephronophthisis-related ciliopathy. Hum Genet 132(8):865–884. doi:10.1007/s00439-013-1297-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was undertaken as part of GENE-ME (a research initiative for investigation of inherited diseases from the Middle-East).

Conflict of interest

None.

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Author notes

    Authors and Affiliations

    1. The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK

      A. Haghighi

    2. Department of Genetics, Harvard Medical School, 77 Ave Louis Pasteur, Boston, MA, 02115, USA

      A. Haghighi

    3. Department of Medicine and the Howard Hughes Medical Institute, Brigham and Women’s Hospital, Boston, MA, USA

      A. Haghighi

    4. Department of Medicine, Firoozgar Hospital, Tehran University of Medical Sciences, Tehran, Iran

      S. Savaj

    5. Faculty of Medicine, Mashhad Azad University, Mashhad, Iran

      H. Haghighi-Kakhki

    6. Centre de Génétique Humaine, Institut de Pathologie et de Génétique, Gosselies, Belgium

      V. Benoit & B. Grisart

    7. Center for Human Genetics, Université Catholique de Louvain, Brussels, Belgium

      K. Dahan

    8. Institute of Pathology and Genetics, Gosselies, Belgium

      K. Dahan

    Authors
    1. A. Haghighi
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    2. S. Savaj
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    Corresponding author

    Correspondence to A. Haghighi.

    Additional information

    S. Savaj and H. Haghighi-Kakhki contributed equally to this work and should be considered joint second authors.

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    Haghighi, A., Savaj, S., Haghighi-Kakhki, H. et al. Identification of an NPHP1 deletion causing adult form of nephronophthisis. Ir J Med Sci 185, 589–595 (2016). https://doi.org/10.1007/s11845-015-1312-7

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    • DOI: https://doi.org/10.1007/s11845-015-1312-7

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