NPHS2 Variation in Sporadic Focal Segmental Glomerulosclerosis

Abstract

Mutations in NPHS2, the gene that encodes podocin, are well-established causes of both familial and sporadic steroid-resistant focal segmental glomerulosclerosis (FSGS) in the pediatric population, but have not been well-characterized in late-onset disease. To investigate the role of NPHS2 polymorphisms in sporadic cases of late-onset FSGS, we studied 377 biopsy-confirmed FSGS cases and 919 controls. We identified 18 single nucleotide polymorphisms (SNPs) by resequencing a subgroup of cases and controls, and subsequently genotyped African-American and European-American cases and controls for five missense SNPs, three SNPs within introns, and four SNPs in the 3Ј untranslated region. No homozygotes or compound heterozygotes were observed for any missense mutation. R138Q carriers were more frequent among FSGS cases relative to controls (OR ϭ 4.9, P ϭ 0.06), but heterozygosity for the other four missense mutations was equally distributed among FSGS cases and controls. Finally, a common haplotype of noncoding SNPs carried by 20% of African-Americans, but not observed in EuropeanAmericans, was strongly associated with a 50% reduction in risk for sporadic FSGS (OR ϭ 0.5, P ϭ 0.001). These results indicate that genetic variation or mutation of NPHS2 may play a role in late-onset sporadic FSGS.

Clinical Value of NPHS2 Analysis in Early- and Adult-Onset Steroid-Resistant Nephrotic Syndrome

“…On the other hand, p.R229Q was present in 4.54% (12 of 132) of cases in heterozygosity and in 0.75% (1 of 132) of cases in homozygosity. p.R229Q has been extensively reported in a higher frequency among patients than in controls, but without statistical significance (17,18,20,21,26). In our Spanish study population, the frequency of the p.R229Q allele was significantly higher in SRNS patients than in controls (5.3 versus 1.9%), which supports the results obtained by Machuca et al (25) among Europeans and South American patients.…”

“…In addition, Tsukaguchi et al (20) reported NPHS2 variants in 23% of late-onset familial cases and in 2% of sporadic ones. In contrast, NPHS2 mutations were not found in four large cohorts of adult-onset cases published subsequently (21)(22)(23)(24). Recently, Machuca et al (25) identified NPHS2 substitutions in 14% of cases presenting with SRNS after 18 years of age.…”

APOL1 Genetic Variants in Focal Segmental Glomerulosclerosis and HIV-Associated Nephropathy

“…The cases and controls have been previously described. 5,25 Primary FSGS and HIVAN cases were enrolled in the NIH FSGS Genetic Study from 22 academic medical centers in the United States. Institutional review boards at each collaborating medical center approved study protocols and each subject provided written informed consent.…”

Podocin Inactivation in Mature Kidneys Causes Focal Segmental Glomerulosclerosis and Nephrotic Syndrome

“…9,10 The NPHS2 gene, which encodes the slit diaphragm protein podocin, not only accounts for 43% of familial and 10% of sporadic forms of nephrotic syndrome, but also some genetic variants may increase the risk for glomerular disease. 11,12 Podocin acts as a structural scaffold in podocyte foot processes and interacts with slit diaphragm proteins to facilitate cellular signaling events. [13][14][15][16] Previously, we described the phenotypic consequences in mice of constitutive absence of podocin or expression of a podocin missense mutant and identified genetic and environmental modifiers of the renal disease.…”