title: Identification of GDNF gene sequence variations in patients with medullary sponge kidney disease.
abstract: OBJECTIVE
  Medullary sponge kidney (MSK) is a rare nephropathy characterized by cystic anomalies of precalyceal ducts, nephrocalcinosis, renal stones, and tubule dysfunctions. Its association with various malformations and cases of familial aggregation supports the conviction that genetic factors are involved, but no genetic studies have been conducted to date. It is hypothesized that MSK is due to a disruption at the "ureteric bud/metanephric blastema" interface caused by critical developmental genes functioning abnormally.
  
  
  METHODS
  Fifty-five apparently sporadic MSK patients were analyzed by direct DNA sequencing of all exons and exon-intron boundaries of glial cell-derived neurotrophic factor (GDNF) gene and rearranged during transfection (RET) gene, which have a leading role in renal development.
  
  
  RESULTS
  Two novel variants were found in heterozygosity in the MSK case population: GDNF{ENST00000344622}:c.-45G>C and c.-27+18G>A in a putative binding domain for paired-box 2 transcription factor. As a whole, eight patients showed these variations: four patients carried the c.[-45G>C; -27+18G>A] complex allele, and the others had the c.-27+18G>A alone. A case-control study revealed that these two alleles were significantly associated with MSK. Five of the eight cases were found to be familial, and the allele variants cosegregated with the disease in a seemingly dominant pattern of inheritance. Patients revealed no mutations in the RET gene.
  
  
  CONCLUSIONS
  This is the first report identifying GDNF gene sequence variations in patients with MSK and suggesting a role for this gene in the pathogenesis of some cases of the disease.
authors.affiliation: Laboratory of Histomorphology and Molecular Biology of the Kidney, Division of Nephrology, Department of Medical and Surgical Sciences, University Hospital of Padua, Via Giustiniani, 2. 35128 Padua, Italy. r.torregrossa@libero.it
authors.forename: Rossella
authors.initials: R
authors.lastname: Torregrossa
authors.forename: Franca
authors.initials: F
authors.lastname: Anglani
authors.forename: Antonia
authors.initials: A
authors.lastname: Fabris
authors.forename: Alessia
authors.initials: A
authors.lastname: Gozzini
authors.forename: Annalisa
authors.initials: A
authors.lastname: Tanini
authors.forename: Dorella
authors.initials: D
authors.lastname: Del Prete
authors.forename: Rosalba
authors.initials: R
authors.lastname: Cristofaro
authors.forename: Lina
authors.initials: L
authors.lastname: Artifoni
authors.forename: Cataldo
authors.initials: C
authors.lastname: Abaterusso
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchionna
authors.forename: Antonio
authors.initials: A
authors.lastname: Lupo
authors.forename: Angela
authors.initials: A
authors.lastname: D'Angelo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
mesh_terms: D015415:Biomarkers / Q000097:blood / Q000652:urine; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics*; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D007438:Introns; D007558:Italy; D008297:Male; D007691:Medullary Sponge Kidney / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015415:Biomarkers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
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