Identification of GDNF gene sequence variations in patients with medullary sponge kidney disease.

Abstract

BACKGROUND AND OBJECTIVES:

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.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:

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: Rossella Torregrossa, Franca Anglani, Antonia Fabris, Alessia Gozzini, Annalisa Tanini, Dorella Del Prete, Rosalba Cristofaro, Lina Artifoni, Cataldo Abaterusso, Nicola Marchionna, Antonio Lupo, Angela D'Angelo, Giovanni Gambaro
• Journal: Clinical journal of the American Society of Nephrology : CJASN (Clin J Am Soc Nephrol) Vol. 5 Issue 7 Pg. 1205-10 (Jul 2010) ISSN: 1555-905X [Electronic] United States
• PMID: 20448065 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Glial Cell Line-Derived Neurotrophic Factor
• Proto-Oncogene Proteins c-ret
• RET protein, human

Topics

• Biomarkers (blood, urine)
• Case-Control Studies
• DNA Mutational Analysis
• Exons
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genetic Variation
• Glial Cell Line-Derived Neurotrophic Factor (genetics)
• Heredity
• Heterozygote
• Humans
• Introns
• Italy
• Male
• Medullary Sponge Kidney (genetics, metabolism, pathology)
• Pedigree
• Phenotype
• Proto-Oncogene Proteins c-ret (genetics)
• Reverse Transcriptase Polymerase Chain Reaction