Skip to main content
SpringerLink
Log in

Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Polycystic kidney disease (PKD) is one of the most common genetic renal diseases and may be inherited in an autosomal dominant or autosomal recessive pattern. Pathogenic variants in two major genes, PKD1 and PKD2, and two rarer genes, GANAB and DNAJB11, cause autosomal dominant PKD (ADPKD). Early onset and severe PKD can occur with PKD1 and PKD2 pathogenic variants and such phenotypes may be modified by second alleles inherited in trans. Homozygous or compound heterozygous hypomorphic PKD1 variants may also cause a moderate to severe disease PKD phenotype.

Methods

Targeted renal gene panel followed by Sanger sequencing of PKD1 gene were employed to investigate molecular causes in early onset PKD patients.

Results

In this study, we report four consanguineous Saudi Arabian families with early onset PKD which were associated with biallelic variants in PKD1 gene.

Conclusions

Our findings confirm that PKD1 alleles may combine to produce severe paediatric onset PKD mimicking the more severe autosomal recessive ciliopathy syndromes associated with PKD. Screening of parents of such children may also reveal subclinical PKD phenotypes.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Torres VE, Harris PC, Pirson Y (2007) Autosomal dominant polycystic kidney disease. Lancet 369:1287–1301

    Article  PubMed  Google Scholar 

  2. Hildebrandt F, Otto E (2005) Cilia and centrosomes: a unifying pathogenic concept for cystic kidney disease? Nat Rev Genet 6:928–940

    Article  CAS  PubMed  Google Scholar 

  3. Igarashi P, Somlo S (2002) Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 13:2384–2398

    Article  CAS  PubMed  Google Scholar 

  4. Hulten M (1988) Linkage heterogeneity in autosomal dominant polycystic kidney disease. Lancet 2:451–452

    Article  CAS  PubMed  Google Scholar 

  5. Kimberling WJ, Fain PR, Kenyon JB, Goldgar D, Sujansky E, Gabow PA (1988) Linkage heterogeneity of autosomal dominant polycystic kidney disease. N Engl J Med 319:913–918

    Article  CAS  PubMed  Google Scholar 

  6. Mochizuki T, Wu G, Hayashi T, Xenophontos SL, Veldhuisen B, Saris JJ, Reynolds DM, Cai Y, Gabow PA, Pierides A, Kimberling WJ, Breuning MH, Deltas CC, Peters DJ, Somlo S (1996) PKD2, a gene for polycystic kidney disease that encodes an integral membrane protein. Science 272:1339–1342

    Article  CAS  PubMed  Google Scholar 

  7. Porath B, Gainullin VG, Cornec-Le Gall E, Dillinger EK, Heyer CM, Hopp K, Edwards ME, Madsen CD, Mauritz SR, Banks CJ, Baheti S, Reddy B, Herrero JI, Banales JM, Hogan MC, Tasic V, Watnick TJ, Chapman AB, Vigneau C, Lavainne F, Audrezet MP, Ferec C, Le Meur Y, Torres VE, Genkyst Study Group HPoPKDG, Consortium for Radiologic Imaging Studies of Polycystic Kidney D, Harris PC (2016) Mutations in GANAB, encoding the glucosidase IIalpha subunit, cause autosomal-dominant polycystic kidney and liver disease. Am J Hum Genet 98:1193–1207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Cornec-Le Gall E, Olson RJ, Besse W, Heyer CM, Gainullin VG, Smith JM, Audrezet MP, Hopp K, Porath B, Shi B, Baheti S, Senum SR, Arroyo J, Madsen CD, Ferec C, Joly D, Jouret F, Fikri-Benbrahim O, Charasse C, Coulibaly JM, Yu AS, Khalili K, Pei Y, Somlo S, Le Meur Y, Torres VE, Harris PC (2018) Monoallelic mutations to DNAJB11 cause atypical autosomal-dominant polycystic kidney disease. Am J Hum Genet 102:832–844

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. The International Polycystic Kidney Disease Consortium (1995) Polycystic kidney disease: the complete structure of the PKD1 gene and its protein. Cell 81:289–298

  10. Harris PC, Torres VE (2009) Polycystic kidney disease. Annu Rev Med 60:321–337

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Schneider MC, Rodriguez AM, Nomura H, Zhou J, Morton CC, Reeders ST, Weremowicz S (1996) A gene similar to PKD1 maps to chromosome 4q22: a candidate gene for PKD2. Genomics 38:1–4

    Article  CAS  PubMed  Google Scholar 

  12. Steinman TI (2012) Polycystic kidney disease: a 2011 update. Curr Opin Nephrol Hypertens 21:189–194

    Article  CAS  PubMed  Google Scholar 

  13. Bergmann C, von Bothmer J, Ortiz Bruchle 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 (2011) Mutations in multiple PKD genes may explain early and severe polycystic kidney disease. J Am Soc Nephrol 22:2047–2056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Oatley P, Talukder MM, Stewart AP, Sandford R, Edwardson JM (2013) Polycystin-2 induces a conformational change in polycystin-1. Biochemistry 52:5280–5287

    Article  CAS  PubMed  Google Scholar 

  15. Hateboer N, v Dijk MA, Bogdanova N, Coto E, Saggar-Malik AK, San Millan JL, Torra R, Breuning M, Ravine D (1999) Comparison of phenotypes of polycystic kidney disease types 1 and 2. European PKD1-PKD2 study group. Lancet 353:103–107

    Article  CAS  PubMed  Google Scholar 

  16. Cornec-Le Gall E, Audrezet MP, Chen JM, Hourmant M, Morin MP, Perrichot R, Charasse C, Whebe B, Renaudineau E, Jousset P, Guillodo MP, Grall-Jezequel A, Saliou P, Ferec C, Le Meur Y (2013) Type of PKD1 mutation influences renal outcome in ADPKD. J Am Soc Nephrol 24:1006–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rossetti S, Harris PC (2007) Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol 18:1374–1380

    Article  CAS  PubMed  Google Scholar 

  18. Vujic M, Heyer CM, Ars E, Hopp K, Markoff A, Orndal C, Rudenhed B, Nasr SH, Torres VE, Torra R, Bogdanova N, Harris PC (2010) Incompletely penetrant PKD1 alleles mimic the renal manifestations of ARPKD. J Am Soc Nephrol 21:1097–1102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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 (2009) Incompletely penetrant PKD1 alleles suggest a role for gene dosage in cyst initiation in polycystic kidney disease. Kidney Int 75:848–855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Halvorson CR, Bremmer MS, Jacobs SC (2010) Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment. Int J Nephrol Renov Dis 3:69–83

    CAS  Google Scholar 

  21. Bergmann C (2015) ARPKD and early manifestations of ADPKD: the original polycystic kidney disease and phenocopies. Pediatr Nephrol 30:15–30

    Article  PubMed  Google Scholar 

  22. Audrezet MP, Corbiere C, Lebbah S, Moriniere V, Broux F, Louillet F, Fischbach M, Zaloszyc A, Cloarec S, Merieau E, Baudouin V, Deschenes G, Roussey G, Maestri S, Visconti C, Boyer O, Abel C, Lahoche A, Randrianaivo H, Bessenay L, Mekahli D, Ouertani I, Decramer S, Ryckenwaert A, Cornec-Le Gall E, Salomon R, Ferec C, Heidet L (2016) Comprehensive PKD1 and PKD2 mutation analysis in prenatal autosomal dominant polycystic kidney disease. J Am Soc Nephrol 27:722–729

    Article  CAS  PubMed  Google Scholar 

  23. Dias T, Sairam S, Kumarasiri S (2014) Ultrasound diagnosis of fetal renal abnormalities. Best Pract Res Clin Obstet Gynaecol 28:403–415

    Article  PubMed  Google Scholar 

  24. Al-Hamed MH, Kurdi W, Alsahan N, Alabdullah Z, Abudraz R, Tulbah M, Alnemer M, Khan R, Al-Jurayb H, Alahmed A, Tahir AI, Khalil D, Edwards N, Al Abdulaziz B, Binhumaid FS, Majid S, Faquih T, El-Kalioby M, Abouelhoda M, Altassan N, Monies D, Meyer B, Sayer JA, Albaqumi M (2016) Genetic spectrum of Saudi Arabian patients with antenatal cystic kidney disease and ciliopathy phenotypes using a targeted renal gene panel. J Med Genet 53:338–347

    Article  CAS  PubMed  Google Scholar 

  25. el-Hazmi MA, al-Swailem AR, Warsy AS, al-Swailem AM, Sulaimani R, al-Meshari AA (1995) Consanguinity among the Saudi Arabian population. J Med Genet 32:623–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yu C, Chang C, Chang F, Ko H, Chen H (2000) Fetal renal volume in normal gestation: a three-dimensional ultrasound study. Ultrasound Med Biol 26:1253–1256

    Article  CAS  PubMed  Google Scholar 

  27. Tan YC, Blumenfeld JD, Anghel R, Donahue S, Belenkaya R, Balina M, Parker T, Levine D, Leonard DG, Rennert H (2009) Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat 30:264–273

    Article  CAS  PubMed  Google Scholar 

  28. Su Q, Hu F, Ge X, Lei J, Yu S, Wang T, Zhou Q, Mei C, Shi Y (2018) Structure of the human PKD1-PKD2 complex. Science 361, Issue 6406

  29. Rossetti S, Hopp K, Sikkink RA, Sundsbak JL, Lee YK, Kubly V, Eckloff BW, Ward CJ, Winearls CG, Torres VE, Harris PC (2012) Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol 23:915–933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hopp K, Ward CJ, Hommerding CJ, Nasr SH, Tuan HF, Gainullin VG, Rossetti S, Torres VE, Harris PC (2012) Functional polycystin-1 dosage governs autosomal dominant polycystic kidney disease severity. J Clin Invest 122:4257–4273

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sattar S, Gleeson JG (2011) The ciliopathies in neuronal development: a clinical approach to investigation of Joubert syndrome and Joubert syndrome-related disorders. Dev Med Child Neurol 53:793–798

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tsai J, Taylor R, Chothia C, Gerstein M (1999) The packing density in proteins: standard radii and volumes. J Mol Biol 290:253–266

    Article  CAS  PubMed  Google Scholar 

  33. Carrera P, Calzavara S, Magistroni R, den Dunnen JT, Rigo F, Stenirri S, Testa F, Messa P, Cerutti R, Scolari F, Izzi C, Edefonti A, Negrisolo S, Benetti E, Alibrandi MT, Manunta P, Boletta A, Ferrari M (2016) Deciphering variability of PKD1 and PKD2 in an Italian cohort of 643 patients with autosomal dominant polycystic kidney disease (ADPKD). Sci Rep 6:30850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wilkes M, Madej MG, Kreuter L, Rhinow D, Heinz V, De Sanctis S, Ruppel S, Richter RM, Joos F, Grieben M, Pike AC, Huiskonen JT, Carpenter EP, Kuhlbrandt W, Witzgall R, Ziegler C (2017) Molecular insights into lipid-assisted ca(2+) regulation of the TRP channel Polycystin-2. Nat Struct Mol Biol 24:123–130

    Article  CAS  PubMed  Google Scholar 

  35. Shen PS, Yang X, DeCaen PG, Liu X, Bulkley D, Clapham DE, Cao E (2016) The structure of the polycystic kidney Disease Channel PKD2 in lipid Nanodiscs. Cell 167:763–773 e711

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Grieben M, Pike AC, Shintre CA, Venturi E, El-Ajouz S, Tessitore A, Shrestha L, Mukhopadhyay S, Mahajan P, Chalk R, Burgess-Brown NA, Sitsapesan R, Huiskonen JT, Carpenter EP (2017) Structure of the polycystic kidney disease TRP channel Polycystin-2 (PC2). Nat Struct Mol Biol 24:114–122

    Article  CAS  PubMed  Google Scholar 

  37. Arthur LL, Chung JJ, Jankirama P, Keefer KM, Kolotilin I, Pavlovic-Djuranovic S, Chalker DL, Grbic V, Green R, Menassa R, True HL, Skeath JB, Djuranovic S (2017) Rapid generation of hypomorphic mutations. Nat Commun 8:14112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank all the families for participating in the study. We also thank all team members at Saudi Human Genome project for help in conducting the study. In addition, we thank sequencing and genotyping core facilities at Genetics Department at the Research Centre, King Faisal Specialist Hospital & Research Centre for performing sequencing.

Author information

Authors and Affiliations

  1. Department of Genetics, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia

    Mohamed H. Al-Hamed, Naderah Altaleb, Wafa Ali, Nouf Al-Numair & Faiqa Imtiaz

  2. Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, P. O. Box 3354, Riyadh, 11211, Saudi Arabia

    Nada Alsahan, Wesam Kurdi & Maha Alnemer

  3. Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, UK

    Sarah J. Rice, Noel Edwards & John A. Sayer

  4. Paediatric Nephrology Department, National Guard Hospital, Almadinah almonawarah, Saudi Arabia

    Eman Nooreddeen & Najd Almejaish

  5. Division of Genetics & Metabolic, King Saud Medical City, Riyadh, Saudi Arabia

    Maha Alotaibi

  6. NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, NE4 5PL, UK

    John A. Sayer

Authors
  1. Mohamed H. Al-Hamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nada Alsahan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sarah J. Rice
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Noel Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eman Nooreddeen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maha Alotaibi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wesam Kurdi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Maha Alnemer
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Naderah Altaleb
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Wafa Ali
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Nouf Al-Numair
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Najd Almejaish
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. John A. Sayer
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Faiqa Imtiaz
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MHA-H, FI and JAS conceived of the study and participated in its design and coordination, and drafted and revised the manuscript. NA-S, WK, EN, MA-O and MA-N participated in the clinical diagnosis of the cases. SJR, NE and NO-N performed in silico analysis and protein modelling. WA, NA-T and NA-M carried out all technical aspects of molecular diagnosis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Faiqa Imtiaz.

Ethics declarations

Conflict of interests

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(PDF 5267 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Hamed, M.H., Alsahan, N., Rice, S.J. et al. Bialleleic PKD1 mutations underlie early-onset autosomal dominant polycystic kidney disease in Saudi Arabian families. Pediatr Nephrol 34, 1615–1623 (2019). https://doi.org/10.1007/s00467-019-04267-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-019-04267-x

Keywords

Search

Navigation