Identification of GDNF gene sequence variations in patients with medullary sponge kidney disease.
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.
Torregrossa
Rossella
R
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
Anglani
Franca
F
Fabris
Antonia
A
Gozzini
Alessia
A
Tanini
Annalisa
A
Del Prete
Dorella
D
Cristofaro
Rosalba
R
Artifoni
Lina
L
Abaterusso
Cataldo
C
Marchionna
Nicola
N
Lupo
Antonio
A
D'Angelo
Angela
A
Gambaro
Giovanni
G
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
D015415:Biomarkers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human
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