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Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis

Abstract

Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.

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Figure 1: Components and organization of the RAS.
Figure 2: Renal pathology and renin expression in individuals with RTD.

References

  1. Allanson, J.E., Pantzar, J.T. & Macleod, P.M. Possible new autosomal recessive syndrome with unusual renal histological changes. Am. J. Med. Genet. 16, 57–60 (1983).

    Article  CAS  Google Scholar 

  2. Allanson, J.E., Hunter, A.G.W., Mettler, G.S. & Jimenez, C. Renal tubular dysgenesis: A not uncommon autosomal recessive syndrome: A review. Am. J. Med. Genet. 43, 811–814 (1992).

    Article  CAS  Google Scholar 

  3. Gubler, M.C., Lacoste, M., Guicharnaud, L. & Mounier, F. Dysgénésie tubulaire rénale et système rénine-angiotensine. Ann. Pédiatr. 42, 608–611 (1995).

    Google Scholar 

  4. Ariel, I. et al. Familial renal tubular dysgenesis: a disorder not isolated to proximal tubules. Pediatr. Pathol. Lab. Med. 15, 915–922 (1995).

    Article  CAS  Google Scholar 

  5. Querfeld, U., Ortmann, M., Vierzig, A. & Roth, B. Renal tubular dysgenesis: a report of two cases. J. Perinatol. 16, 498–500 (1996).

    CAS  PubMed  Google Scholar 

  6. McFadden, D.E., Pantzar, J.T., Van Allen, M.I.I. & Langlois, S. Renal tubular dysgenesis with calvaria hypoplasia: report of two additional cases and review. J. Med. Genet. 34, 846–848 (1997).

    Article  CAS  Google Scholar 

  7. Kumar, D., Moss, G., Primhak, R. & Coombs, R. Congenital renal tubular dysplasia and skull ossification defects similar to teratogenic effects of angiotensin converting enzyme (ACE) inhibitors. J. Med. Genet. 34, 541–545 (1997).

    Article  CAS  Google Scholar 

  8. Kriegsmann, J. et al. Renal tubular dysgenesis (RTD). An important cause of the oligo-hydramnion-sequence. Report of 3 cases and review of the literature. Pathol. Res. Pract. 196, 861–865 (2000).

    Article  CAS  Google Scholar 

  9. Kemper, M.J. et al. Antenatal oligohydramnios of renal origin: postnatal therapeutic and prognostic challenges. Clin. Nephrol. 56, S9–S12 (2001).

    CAS  PubMed  Google Scholar 

  10. Seyle, H. Transformation of the kidney into an exclusively endocrin organ. Nature 158, 131 (1946).

    Article  Google Scholar 

  11. Landing, B.H., Ang, S.M., Herta, N., Larson, E.F. & Turner, M. Labeled lectin studies of renal tubular dysgenesis and renal tubular atrophy of postnatal renal ischemia and end-stage kidney disease. Pediatr. Pathol. 14, 87–99 (1994).

    Article  CAS  Google Scholar 

  12. Marcussen, N. Atubular glomeruli in renal artery stenosis. Lab. Invest. 65, 558–565 (1991).

    CAS  PubMed  Google Scholar 

  13. Genest, D.R. & Lage, J.M. Absence of normal-appearing proximal tubules in the fetal and neonatal kidney: Prevalence and significance. Hum. Pathol. 22, 147–153 (1991).

    Article  CAS  Google Scholar 

  14. Mahieu-Caputo, D. et al. Twin to twin transfusion syndrome. Role of the fetal renin-angiotensin system. Am. J. Pathol. 156, 629–636 (2000).

    Article  CAS  Google Scholar 

  15. Johal, J.S., Thorp, J.W. & Oyer, C.E. Neonatal hemochromatosis, renal tubular dysgenesis, and hypocalvaria in a neonate. Pediatr. Dev. Pathol. 1, 433–437 (1998).

    Article  CAS  Google Scholar 

  16. Barr, M. Jr. & Cohen, M. Jr. ACE inhibitor fetopathy and hypocalvaria: the kidney-skull connection. Teratology 44, 485–495 (1991).

    Article  CAS  Google Scholar 

  17. Martinovic, J., Benachi, A., Laurent, N., Daïkha-Dahmane, F. & Gubler, M.C. Fetal toxic effects of angiotensin II receptor antagonists. Report of three additional cases. Lancet 358, 241–242 (2001).

    Article  CAS  Google Scholar 

  18. Schütz, S., Le Moullec, J.M., Corvol, P. & Gasc, J.M. Early expression of all components of the renin-angiotensin-system in human development. Am. J. Pathol. 149, 2067–2079 (1996).

    PubMed  PubMed Central  Google Scholar 

  19. Tufro-McReddie, A. & Gomez, R.A. Ontogeny of the renin-angiotensin system. Semin. Nephrol. 13, 519–530 (1993).

    CAS  PubMed  Google Scholar 

  20. Reese, M.G., Eeckman, F.H., Kulp, D. & Haussler, D. Improved splice site detection in Genie. J. Comput. Biol 4, 311–323 (1997).

    Article  CAS  Google Scholar 

  21. Morris, B.J. et al. Human renin gene sequence, gene regulation and prorenin processing. J. Hypertens. 2, suppl. 3, 231–233 (1984).

    CAS  Google Scholar 

  22. Ng, P.C. & Henikoff, S. Predicting deleterious amino acid substitutions. Genome Res. 11, 863–874 (2001).

    Article  CAS  Google Scholar 

  23. Gaillard, I., Clauser, E. & Corvol, P. Structure of human angiotensinogen gene. DNA 8, 87–99 (1989).

    Article  CAS  Google Scholar 

  24. Streatfeild-James, R.M. et al. Angiotensinogen cleavage by renin: importance of a structurally constrained N-terminus. FEBS Lett. 436, 267–270 (1998).

    Article  CAS  Google Scholar 

  25. Miura, S., Saku, K. & Karnik, S.S. Molecular analysis of the structure and function of the angiotensin II type 1 receptor. Hypertens. Res. 26, 937–943 (2003).

    Article  CAS  Google Scholar 

  26. Hubert, C., Houot, A.M., Corvol, P. & Soubrier, F. Structure of the angiotensin I-converting enzyme gene. Two alternate promoters correspond to evolutionary steps of a duplicated gene. J. Biol. Chem. 266, 15377–15383 (1991).

    CAS  PubMed  Google Scholar 

  27. Tufro-McReddie, A. et al. Angiotensin II type 1 receptor: role in renal growth and gene expression during normal development. Am. J. Physiol. 266, F911–F918 (1994).

    Article  CAS  Google Scholar 

  28. Sequeira Lopez, M.L., Pentz, E.S., Nomasa, T., Smithies, O. & Gomez, R.A. Renin cells are precursors for multiple cell types that switch to the renin phenotype when homeostasis is threatened. Dev. Cell 6, 719–728 (2004).

    Article  Google Scholar 

  29. Takahashi, N. & Smithies, O. Human genetics, animal models and computer simulations for studying hypertension. Trends Genet. 20, 136–145 (2004).

    Article  CAS  Google Scholar 

  30. Nishimura, H. et al. Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol. Cell 3, 1–10 (1999).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank the affected families for their participation; the members of the Société Française de Foetopathologie for their contribution; P. Corvol and J.M. Gasc for the antibodies to renin and the recombinant plasmids containing the human renin sequence; E. Esquivel, F. Terzi and L. Heidet for critical reading of the manuscript; and G. Delrue and B. Chemani for figure preparation. This work was supported by the Institut National de la Santé et de la Recherche Médicale and by grants from the Association pour l'Utilisation du Rein Artificiel and the Association pour l'Information et la Recherche sur les Maladies Rénales Génétiques.

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Correspondence to Marie Claire Gubler.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Pedigrees of the five consanguineous families with autosomal recessive renal tubular dysgenesis. (PDF 397 kb)

Supplementary Fig. 2

Multiple protein sequence alignment of RAS proteins. (PDF 635 kb)

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Gribouval, O., Gonzales, M., Neuhaus, T. et al. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet 37, 964–968 (2005). https://doi.org/10.1038/ng1623

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