Identification of podocin (NPHS2) gene mutations in African Americans with nondiabetic end-stage renal disease.

Background: Podocin, encoded by NPHS2 and mapped to 1q25.2, is an integral membrane protein exclusively expressed in glomerular podocytes. Mutations in the NPHS2 gene cause autosomal-recessive nephrotic syndrome and have been associated with proteinuria in several populations. Evidence for linkage of end-stage renal disease (ESRD) to chromosome 1q25-31 in the region of NPHS2 has been identified in a genome-wide scan in African American (AA) siblings.

Methods: To investigate the potential role of this gene in ESRD, we sequenced all coding regions and approximately 2 kb of upstream promoter sequence of NPHS2 in 96 unrelated AA nondiabetic ESRD cases and 96 healthy population-based AA controls, and assessed several single nucleotide polymorphisms (SNPs) for association in a larger case-control sample.

Results: Fifty-five variants were identified with minor allele frequencies ranging from <1% to 44%. Twenty-three polymorphisms were located in the promoter region, 11 were exonic, 13 were intronic, and 8 were in the 5' and 3'- untranslated regions. Two novel nonsynonymous coding SNPs were identified (A44E and A61V). An insertion polymorphism in intron 3, IVS3+9insA, was detected in 6 ESRD patients and in no controls. This variant, and 4 other common SNPs, were evaluated in a larger sample of 288 AA ESRD cases and 278 AA controls. The overall minor allele frequencies for the insertion allele were 0.018 in cases and 0.002 in controls. Significant evidence of association of IVS3+9insA was observed (P= 0.012), and the haplotype containing the insertion allele in cases was also associated.

Conclusion: These results suggest that uncommon variants of the NPHS2 gene may play a role in the development of nondiabetic ESRD in AAs.