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
- evolutionary conserved non-coding regions
- molecular genetics
- renal medicine
Statistics from Altmetric.com
↵* 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.