RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects

Cécile Jeanpierre (1) , Guillaume Macé (1) , Mélanie Parisot (1) , Vincent Morinière (2, 3) , Audrey Pawtowsky (2) , Marion Benabou (1) , Jelena Martinovic (4) , Jeanne Amiel (5) , Tania Attié-Bitach (5) , Anne-Lise Delezoide (6) , Philippe Loget (7) , Patricia Blanchet (8) , Dominique Gaillard (9, 10) , Marie Gonzales (11) , Wassila Carpentier (12) , Patrick Nitschke (13) , Frederic Tores (13) , Laurence Heidet (2, 3) , Corinne Antignac (1, 2) , Remi Salomon (1, 3, 14)

1 UMR_S 983 - Néphropathies héréditaires et rein en développement
2 Service de Génétique Médicale [CHU Necker]
3 MARHEA - Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte [CHU-Necker]
4 Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
5 Inserm U781 - Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement
6 Service de biologie du développement[Debré]
7 Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes]
8 Service de génétique et de foetopathologie
9 Service de génétique [Reims]
10 Dynamique cellulaire et moléculaire de la muqueuse respiratoire
11 CHU Trousseau [APHP]
12 P3S - Plateforme Post-génomique de la Pitié-Salpêtrière
13 Plateforme de bioinformatique
14 Service de néphrologie pédiatrique [CHU Necker]

Background The RET/GDNF signalling pathway plays a crucial role during development of kidneys and 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 better characterize the involvement of RET and GDNF in kidney development defects, we studied a series of 105 fetuses with bilateral defects including renal agenesis, severe hypodysplasia or multicystic dysplastic kidney. RET and GDNF coding sequences, evolutionary conserved non-coding regions (ECRs) in promoters, 3'UTRs and RET intron 1 were analysed. Copy number variations (CNVs) at these loci were also investigated. Results We identified: (i) a low frequency (< 7%) of potential mutations in the RET coding sequence, with inheritance from the healthy father for four of them; (ii) no GDNF mutation; (iii) similar allele frequencies in patients and controls for most SNP 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); (iv) distribution of the few rare RET variants unidentified in controls into the various 5'-ECRs; (v) absence of CNVs. 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.

Mots clés: renal agenesis; renal hypodysplasia; variants; evolutionary conserved non-coding regions; CNVs

Cécile Jeanpierre, Guillaume Macé, Mélanie Parisot, Vincent Morinière, Audrey Pawtowsky, et al.. RET and GDNF mutations are rare in fetuses with renal agenesis or other severe kidney development defects. Journal of Medical Genetics, 2011, 48 (7), pp.497. ⟨10.1136/jmg.2010.088526⟩. ⟨hal-00622876⟩