Pediatric Nephrology

, Volume 24, Issue 6, pp 1151–1157 | Cite as

Common variants of the glial cell-derived neurotrophic factor gene do not influence kidney size of the healthy newborn

  • Zhao Zhang
  • Jackie Quinlan
  • David Grote
  • Mathieu Lemire
  • Thomas Hudson
  • Alice Benjamin
  • Anne Roy
  • Elena Pascuet
  • Meigan Goodyer
  • Chandhana Raju
  • Fiona Houghton
  • Maxime Bouchard
  • Paul Goodyer
Original Article

Abstract

Glial cell-derived neurotrophic factor (GDNF) plays an important role in renal development, serving as a trophic factor for outgrowth of the ureteric bud and its continued arborisation. Our previous studies have shown that common variants of the human paired-box 2 (PAX2) gene (a transcriptional activator of GDNF) and rearranged during transfection (RET) gene (encoding the cognate receptor for GDNF) are associated with a subtle reduction in the kidney size of newborns. Since heterozygosity for a mutant GDNF allele causes mild renal hypoplasia and modest hypertension in mice, we considered the possibility that common variants of the GDNF gene might also contribute to renal hypoplasia in humans. We studied the relationship between newborn renal size or umbilical cord cystatin C and 19 common GDNF gene variants [minor allele frequency (MAF) >5%], three single nucleotide polymorphisms (SNPs) related to a putative PAX binding site and one rare SNP (rs36119840 A/G) which changes an amino acid (R93W), based on data from the haplotype map of the human genome (HapMap). However, none of these 23 SNPs was associated with reduced newborn kidney size or function. Among the 163 Caucasians in our cohort, none had the R93W allele.

Keywords

Glial cell-derived neurotrophic factor (GDNF) Haplotype map of the human genome (HapMap) Renal hypoplasia Branching morphogenesis Nephron number 

References

  1. 1.
    Costantini F, Shakya R (2006) GDNF/Ret signaling and the development of the kidney. Bioessays 28:117–127PubMedCrossRefGoogle Scholar
  2. 2.
    Shakya R, Watanabe T, Costantini F (2005) The role of GDNF/Ret signaling in ureteric bud cell fate and branching morphogenesis. Dev Cell 8:65–74PubMedCrossRefGoogle Scholar
  3. 3.
    Pepicelli CV, Kispert A, Rowitch DH, McMahon AP (1997) GDNF induces branching and increased cell proliferation in the ureter of the mouse. Dev Biol 192:193–198PubMedCrossRefGoogle Scholar
  4. 4.
    Nyengaard JR, Bendtsen TF (1992) Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 232:194–201PubMedCrossRefGoogle Scholar
  5. 5.
    Keller G, Zimmer G, Mall G, Ritz E, Amann K (2003) Nephron number in patients with primary hypertension. N Engl J Med 348:101–108PubMedCrossRefGoogle Scholar
  6. 6.
    Hoy WE, Hughson MD, Singh GR, Douglas-Denton R, Bertram JF (2006) Reduced nephron number and glomerulomegaly in Australian Aborigines: a group at high risk for renal disease and hypertension. Kidney Int 70:104–110PubMedCrossRefGoogle Scholar
  7. 7.
    Hoy WE, Bertram JF, Denton RD, Zimanyi M, Samuel T, Hughson MD (2008) Nephron number, glomerular volume, renal disease and hypertension. Curr Opin Nephrol Hypertens 17:258–265PubMedCrossRefGoogle Scholar
  8. 8.
    Pichel JG, Shen L, Sheng HZ, Granholm AC, Drago J, Grinberg A, Lee EJ, Huang SP, Saarma M, Hoffer BJ, Sariola H, Westphal H (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76PubMedCrossRefGoogle Scholar
  9. 9.
    Moore MW, Klein RD, Farinas I, Sauer H, Armanini M, Phillips H, Reichardt LF, Ryan AM, Carver-Moore K, Rosenthal A (1996) Renal and neuronal abnormalities in mice lacking GDNF. Nature 382:76–79PubMedCrossRefGoogle Scholar
  10. 10.
    Sanchez MP, Silos-Santiago I, Frisen J, He B, Lira SA, Barbacid M (1996) Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382:70–73PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang Z, Quinlan J, Hoy W, Hughson MD, Lemire M, Hudson T, Hueber PA, Benjamin A, Roy A, Pascuet E, Goodyer M, Raju C, Houghton F, Bertram J, Goodyer P (2008) A common RET variant is associated with reduced newborn kidney size and function. J Am Soc Nephrol 19:2027–2034PubMedCrossRefGoogle Scholar
  12. 12.
    Quinlan J, Lemire M, Hudson T, Qu H, Benjamin A, Roy A, Pascuet E, Goodyer M, Raju C, Zhang Z, Houghton F, Goodyer P (2007) A common variant of the PAX2 gene is associated with reduced newborn kidney size. J Am Soc Nephrol 18:1915–1921PubMedCrossRefGoogle Scholar
  13. 13.
    Mosteller RD (1987) Simplified calculation of body-surface area. N Engl J Med 317:1098PubMedGoogle Scholar
  14. 14.
    Harmoinen A, Ylinen E, Ala-Houhala M, Janas M, Kaila M, Kouri T (2000) Reference intervals for cystatin C in pre- and full-term infants and children. Pediatr Nephrol 15:105–108PubMedCrossRefGoogle Scholar
  15. 15.
    Narlis M, Grote D, Gaitan Y, Boualia SK, Bouchard M (2007) Pax2 and pax8 regulate branching morphogenesis and nephron differentiation in the developing kidney. J Am Soc Nephrol 18:1121–1129PubMedCrossRefGoogle Scholar
  16. 16.
    Cullen-McEwen LA, Kett MM, Dowling J, Anderson WP, Bertram JF (2003) Nephron number, renal function, and arterial pressure in aged GDNF heterozygous mice. Hypertension 41:335–340PubMedCrossRefGoogle Scholar
  17. 17.
    Grimm L, Holinski-Feder E, Teodoridis J, Scheffer B, Schindelhauer D, Meitinger T, Ueffing M (1998) Analysis of the human GDNF gene reveals an inducible promoter, three exons, a triplet repeat within the 3′-UTR and alternative splice products. Hum Mol Genet 7:1873–1886PubMedCrossRefGoogle Scholar
  18. 18.
    Angrist M, Bolk S, Halushka M, Lapchak PA, Chakravarti A (1996) Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet 14:341–344PubMedCrossRefGoogle Scholar
  19. 19.
    Salomon R, Attie T, Pelet A, Bidaud C, Eng C, Amiel J, Sarnacki S, Goulet O, Ricour C, Nihoul-Fekete C, Munnich A, Lyonnet S (1996) Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease. Nat Genet 14:345–347PubMedCrossRefGoogle Scholar
  20. 20.
    Skinner MA, Safford SD, Reeves JG, Jackson ME, Freemerman AJ (2008) Renal aplasia in humans is associated with RET mutations. Am J Hum Genet 82:344–351PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2008

Authors and Affiliations

  • Zhao Zhang
    • 1
  • Jackie Quinlan
    • 1
  • David Grote
    • 2
  • Mathieu Lemire
    • 3
  • Thomas Hudson
    • 3
  • Alice Benjamin
    • 4
  • Anne Roy
    • 5
  • Elena Pascuet
    • 1
  • Meigan Goodyer
    • 1
  • Chandhana Raju
    • 1
  • Fiona Houghton
    • 1
  • Maxime Bouchard
    • 2
  • Paul Goodyer
    • 1
    • 6
  1. 1.McGill University Montreal Children’s Hospital Research InstituteMontrealCanada
  2. 2.McGill University McGill Cancer CenterMontrealCanada
  3. 3.Ontario Institute for Cancer ResearchTorontoCanada
  4. 4.Department of Obstetrics and GynecologyMcGill UniversityMontrealCanada
  5. 5.Department of RadiologyMcGill UniversityMontrealCanada
  6. 6.MontrealCanada

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