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

• Published in: Journal of medical genetics Vol. 48; no. 7; pp. 497 - 504
• Main Authors: Jeanpierre, Cécile, Macé, Guillaume, Parisot, Mélanie, Morinière, Vincent, Pawtowsky, Audrey, Benabou, Marion, Martinovic, Jelena, Amiel, Jeanne, Attié-Bitach, Tania, Delezoide, Anne-Lise, Loget, Philippe, Blanchet, Patricia, Gaillard, Dominique, Gonzales, Marie, Carpentier, Wassila, Nitschke, Patrick, Tores, Frédéric, Heidet, Laurence, Antignac, Corinne, Salomon, Rémi
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01.07.2011; BMJ Publishing Group; BMJ Publishing Group LTD
• Subjects: Alleles; Biological and medical sciences; CNVs; Congenital Abnormalities - genetics; Cysts; DNA Copy Number Variations; evolutionary conserved non-coding regions; Fetus - abnormalities; Fetuses; Gene Expression Regulation, Developmental; Glial Cell Line-Derived Neurotrophic Factor - genetics; Humans; Kidney - abnormalities; Kidney Diseases - congenital; Kidney Diseases - genetics; Kidneys; Kinases; Malformations of the urinary system; Medical sciences; molecular genetics; Mutation; Mutation - genetics; Nephrology. Urinary tract diseases; Open Reading Frames - genetics; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins c-ret - genetics; Renal agenesis; renal hypodysplasia; renal medicine; Signal Transduction - genetics; variants; Kidney disease; Urinary system disease; Malformation; Kidney agenesis; Development; Fetus; Mutation; Severe; Congenital disease; Kidney; variants; evolutionary conserved non-coding regions; renal hypodysplasia; renal agenesis; CNVs
• ISSN: 0022-2593; 1468-6244
• DOI: 10.1136/jmg.2010.088526

BackgroundThe 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 methodsTo 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.ResultsThe 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.ConclusionThese 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.