The Association of Podocin R229Q Polymorphism With Increased Albuminuria or Reduced Estimated GFR in a Large Population-Based Sample of US Adults

Köttgen, Anna; Hsu, Charles C.; Coresh, Josef; Shuldiner, Alan R.; Berthier-Schaad, Yvette; Gambhir, Tejal Rami; Smith, Michael W.; Boerwinkle, Eric; Kao, W. H. Linda

doi:10.1053/j.ajkd.2008.02.306

Cited by 29 publications

(22 citation statements)

References 26 publications

(5 reference statements)

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“…Additionally, Pereira et al [8] reported that R229Q is responsible for microalbuminuria in the general population. On the other hand, Kottgen et al [14] did not corroborate any significant association between R229Q and GFR in either white or black individuals. Based on a very detailed review and meta-analysis by Franceschini et al [15], the R229Q variant gives a nonsignificant increased risk for FSGS by 20-70% in European descent populations.…”

Section: Resultsmentioning

confidence: 88%

Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria

et al. 2012

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Section: Resultsmentioning

confidence: 88%

Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria

et al. 2012

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“…In contrary, Tonna et al [33] found that p.Arg229Gln does not alter the risk of proteinuria in the general population. Köttgen et al [34] did not corroborate any significant association between p.Arg229Gln and GFR in either white or black individuals. Based on a very detailed review and meta-analysis article by Franceschini et al [35], the p.Arg229Gln variant gives a non-significant increased risk for FSGS by 20 to 70% in populations of European descent.…”

Section: Discussionmentioning

confidence: 94%

Co-Inheritance of Functional Podocin Variants with Heterozygous Collagen IV Mutations Predisposes to Renal Failure

Stefanou

Pieri

Savva

et al. 2015

Nephron

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Background/Aims: A subset of patients who present with proteinuria and are diagnosed with focal segmental glomerulosclerosis (FSGS) have inherited heterozygous COL4A3/A4 mutations and are also diagnosed with thin basement membrane nephropathy (TBMN-OMIM: 141200). Two studies showed that co-inheritance of NPHS2-p.Arg229Gln, a podocin variant, may increase the risk for proteinuria and renal function decline. Methods: We hypothesized that additional podocin variants may exert a similar effect. We studied genetically a well-characterized Cypriot TBMN patient cohort by re-sequencing the NPHS2 coding region. We also performed functional studies in cell culture experiments, investigating the interaction of podocin variants with itself and with nephrin. Results: Potentially disease-modifying podocin variants were searched for by analyzing NPHS2 in 35 ‘severe' TBMN patients. One non-synonymous variant, p.Glu237Gln, was detected. Both variants, p.Arg229Gln and p.Glu237Gln, were tested in a larger cohort of 122 TBMN patients, who were categorized as ‘mild' or ‘severe' based on the presence of microscopic hematuria alone or combined with chronic renal failure and/or proteinuria. Seven ‘severe' patients carried either of the 2 variants; none was present in the ‘mild' patients (p = 0.05, Pearson χ²). The 7 carriers belong in 2 families segregating mutation COL4A3-p.Gly1334Glu. Inheritance of the wild-type (WT) and mutant alleles correlated with the phenotype (combined concordance probability 0.003). Immunofluorescence (IF) experiments after dual co-transfection of WT and mutant podocin suggested altered co-localization of mutant homodimers. IF experiments after co-transfection of WT podocin and nephrin showed normal membrane localization, while both podocin variants interfered with normal trafficking, demonstrating perinuclear staining. Immunoprecipitation experiments showed stronger binding of mutant podocin to WT podocin or nephrin. Conclusion: The results support the hypothesis that certain hypomorphic podocin variants may act as adverse genetic modifiers when co-inherited with COL4A3/A4 mutations, thus predisposing to FSGS and severe kidney function decline.

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“…Kottgen et al [16] did not find a significant association of this sequence variant and albumin-creatinine ratio or estimated glomerular filtration rate in either white or black individuals. However, a recent study suggests that patients carrying this sequence variant, in combination with a pathogenic NPHS2 mutation develop FSGS [17,18].…”

Section: Discussionmentioning

confidence: 98%

Truncating <b><i>Wilms Tumor Suppressor Gene 1</i></b> Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report

Hoefele

Kemper²,

Schoenermarck³

et al. 2016

Nephron

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About 30% of children with nephrotic syndrome (NS) have inherited forms. Among them, mutations in Wilms tumor suppressor gene 1 (WT1) are a well characterized cause associated with steroid-resistant NS, Wilms tumor, and urogenital malformation in males. However, the role of WT1 mutations in adult-onset focal segmental glomerulosclerosis (FSGS) is unclear. We report the case of a 38-year-old female with FSGS. She had been diagnosed with streak ovaries during diagnostic workup for infertility. Mutational analysis identified the heterozygous mutation c.1372C>T (p.Arg458*) in WT1 and the heterozygous non-neutral polymorphism c.868G>A (p.Arg229Gln) in NPHS2. Chromosomal analysis revealed a normal 46,XX female karyotype. Our case highlights that WT1 mutations should be considered in XX females with adult-onset FSGS, especially if urogenital abnormalities are present.

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The Association of Podocin R229Q Polymorphism With Increased Albuminuria or Reduced Estimated GFR in a Large Population-Based Sample of US Adults

Cited by 29 publications

References 26 publications

Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria

Evidence that NPHS2-R229Q predisposes to proteinuria and renal failure in familial hematuria

Co-Inheritance of Functional Podocin Variants with Heterozygous Collagen IV Mutations Predisposes to Renal Failure

Truncating <b><i>Wilms Tumor Suppressor Gene 1</i></b> Mutation in an XX Female with Adult-Onset Focal Segmental Glomerulosclerosis and Streak Ovaries: A Case Report

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