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RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects
  1. Cécile Jeanpierre1,2,
  2. Guillaume Macé1,2,
  3. Mélanie Parisot1,2,
  4. Vincent Morinière3,4,
  5. Audrey Pawtowsky3,
  6. Marion Benabou1,2,
  7. Jelena Martinovic5,
  8. Jeanne Amiel2,6,
  9. Tania Attié-Bitach2,6,
  10. Anne-Lise Delezoide7,8,
  11. Philippe Loget9,
  12. Patricia Blanchet10,
  13. Dominique Gaillard11,
  14. Marie Gonzales12,13,
  15. Wassila Carpentier13,14,
  16. Patrick Nitschke15,
  17. Frédéric Tores15,
  18. Laurence Heidet3,4,
  19. Corinne Antignac1,2,3,
  20. Rémi Salomon1,2,4,16,
  21. the Société Française de Foetopathologie*
  1. 1Inserm U983, Hôpital Necker, Paris, France
  2. 2Université Paris Descartes, Paris, France
  3. 3AP-HP, Département de Génétique, Hôpital Necker, Paris, France
  4. 4AP-HP, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Hôpital Necker, Paris, France
  5. 5AP-HP, Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker, Paris, France
  6. 6Inserm U781, Hôpital Necker, Paris, France
  7. 7AP-HP, Service de Biologie du développement, Hôpital Robert Debré, Paris, France
  8. 8Université Paris Diderot, Paris, France
  9. 9Département d'Anatomie et de Cytologie Pathologiques, Centre Hospitalier de Pontchaillou, Rennes, France
  10. 10Service de Génétique et de Foetopathologie, Hôpital Arnaud de Villeneuve, Montpellier, France
  11. 11Service de Génétique, Centre Hospitalier Universitaire de Reims, Inserm U 903, Reims, France
  12. 12AP-HP, Service de Génétique et Embryologie médicales, Hôpital Armand Trousseau, Paris, France
  13. 13Université Paris Pierre et Marie Curie, Paris, France
  14. 14Plateforme Post-Génomique P3S, Hôpital Pitié-Salpêtrière, Paris, France
  15. 15Plateforme de Bioinformatique de l'Université Paris Descartes, Paris, France
  16. 16AP-HP, Service de Néphrologie Pédiatrique, Hôpital Necker, Paris, France
  1. Correspondence to Dr Cécile Jeanpierre, Inserm U983, Hôpital Necker, 75015 Paris, France; cecile.jeanpierre{at}


Background The RET/GDNF signalling pathway plays a crucial role during development of the kidneys and the enteric nervous system. In humans, RET activating mutations cause multiple endocrine neoplasia, whereas inactivating mutations are responsible for Hirschsprung disease. RET mutations have also been reported in fetuses with renal agenesis, based on analysis of a small series of samples.

Objective and methods To characterise better the involvement of RET and GDNF in kidney development defects, a series of 105 fetuses with bilateral defects, including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney, was studied. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3′UTRs, and RET intron 1 were analysed. Copy number variations at these loci were also investigated.

Results The study identified: (1) a low frequency (<7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (2) no GDNF mutation; (3) similar allele frequencies in patients and controls for most single nucleotide polymorphism variants, except for RET intron 1 variant rs2506012 that was significantly more frequent in affected fetuses than in controls (6% vs 2%, p=0.01); (4) distribution of the few rare RET variants unidentified in controls into the various 5′-ECRs; (5) absence of copy number variations.

Conclusion These results suggest that genomic alteration of RET or GDNF is not a major mechanism leading to renal agenesis and other severe kidney development defects. Analysis of a larger series of patients will be necessary to validate the association of the RET intron 1 variant rs2506012 with renal development defects.

  • Renal agenesis
  • renal hypodysplasia
  • variants
  • evolutionary conserved non-coding regions
  • CNVs
  • molecular genetics
  • renal medicine

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  • * The members of the Société Française de Foetopathologie who provided fetal tissues are: E Alanio, CHU Reims; J Aziza, CHU Purpan, Toulouse; B Bessières, Institut de Puériculture, Paris; N Bigi, CHU Montpellier; R Bouvier, Centre de Pathologie Est, Bron; M Bucourt, Hôpital Jean Verdier, Bondy; M Danjoux, CHU Purpan, Toulouse; D Carles, CHU Pellegrin, Bordeaux; A Clemenson, CHU St Etienne; F Cornelis, Hôpital Jean Verdier, Bondy; M Danjoux, CHU Purpan, Toulouse; F Dijoud, Hôpital de la Croix Rousse, Lyon; O Esperandieu, CH Orléans; B Foliguet, CHU Nancy; R Grigorescu, Hôpital Armand Trousseau, Paris;F Guimiot, Hôpital Robert Debré, Paris; V Hennequin, CHU Nancy; S Khung-Savatovsky, Hôpital Robert Debré, Paris; N Laurent, CHU Dijon; L Loeuillet, CHI Poissy; P Marcorelles, CHU Brest; A-E Mas, Hôpital A Béclère, Clamart; J-P Masutti, CHU Nancy; C Mechler, CHU Louis Mourier, Colomb; M-J Perez, CHU Montpellier; I Pommepuy, CHU Limoges; M-H Saint Frison, CH Victor Dupouy, Argenteuil;M Sinico, CHI Créteil; J Tantau, Groupe hospitalier Cochin-St Vincent de Paul, Paris

  • Funding This work was supported by Institut National de la Santé et de la Recherche Médicale, Agence Nationale de la Recherche (ANR 06-MPAR-034-01), GIS-Institut des Maladies Rares (AAE07007KSA) and Programme Hospitalier de la Recherche Clinique Assistance Publique (AOM07129).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Comité de Protection des Personnes pour la Recherche Biomédicale Ile de France 2.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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