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

Voskarides, Konstantinos; Arsali, Maria; Athanasiou, Yiannis; Elia, Avraam; Pierides, Alkis; Deltas, Constantinos

doi:10.1007/s00467-011-2084-6

Cited by 52 publications

(43 citation statements)

References 15 publications

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“…In Cyprus, we found a frequency of 2% for the p.Arg229Gln allele [18] and a frequency of 2.1% for the p.Glu237Gln allele (4 heterozygous in 96 DNA samples of the general population studied here). Contrary to what is available for variant p.Arg229Gln, bibliographical information about p.Glu237Gln is scanty.…”

Section: Discussionmentioning

confidence: 99%

“…Extended founder effects found in Cyprus for 2 mutations in the COL4A3 gene can greatly help in identifying modifier variants due to less prominent genetic background ‘noise'. Previously published data [17,18] encouraged us to proceed in direct re-sequencing of the entire coding region of the NPHS2 gene in ‘severe' patients, with the hope to identify more candidate modifier variants. We found 7 patients with severe phenotype that carried variant p.Arg229Gln or p.Glu237Gln, while none of the mildly affected patients had inherited any non-synonymous variant of obvious significance (p = 0.05).…”

Section: Discussionmentioning

confidence: 99%

“…Two different studies have demonstrated that variant p.Arg229Gln in podocin, encoded by the NPHS2 gene, predisposes TBMN patients to proteinuria and renal failure [17,18]. Pathogenic podocin mutations are responsible for the steroid-resistant nephrotic syndrome (SRNS-OMIM: 600995), which follows the autosomal recessive mode of inheritance.…”

Section: Introductionmentioning

confidence: 99%

“…Here, we used a previously described TBMN cohort [18] that was enriched with enrolment of additional patients and we focused on families that segregate TBMN due to a primary founder mutation COL4A3 -p.Gly1334Glu. We also searched for additional putative variants in the NPHS2 gene that might account for the intrafamilial variability by conferring higher risk.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The patient's mother had negative urine findings with the same mutation of COL4A4. The different phenotype of the same mutation may be explained by the involvement of chemical mediators or other structural proteins, such as the glomerular podocyte, which may interact with type IV collagen [6,7]. Our patient's phenomena that he showed mild to nephrotic-range proteinuria only in various episodes of acute infection may suggest the involvement of chemical mediators such as cytokine or chemokine.…”

Section: Case Reportmentioning

confidence: 76%

Nephrotic-range proteinuria in an infant with thin basement membrane nephropathy

et al. 2013

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Thin basement membrane nephropathy (TBMN) with heterozygous COL4A3/COL4A4 mutations is considered to be a cause of benign familial hematuria. The disease has been believed to have excellent prognosis and TBMN in early childhood is rarely associated with nephrotic-range proteinuria. Furthermore, the presence of proteinuria in patients with TBMN is associated with autosomal-dominant Alport syndrome, which has poorer prognosis in later life. We present an infant case of nephrotic-range proteinuria associated with TBMN caused by heterozygous COL4A4 mutation. A previously healthy 3-year-old boy developed microhematuria and nephroticrange proteinuria. Renal pathology simply revealed thinning of the glomerular basement membrane (GBM) and mutational analysis revealed a novel heterozygous mutation in COL4A4. He was treated with lisinopril for 1.5 years, which resolved his proteinuria and hematuria. At the most recent follow-up at 6.5 years of age, urinalysis and kidney function were completely normal, without requiring medication. However, transient but repeated moderate to nephrotic-range proteinuria and microscopic hematuria occurred in association with other illnesses. This case highlights the spectrum of phenotypes that may be apparent in an infant with TBMN. Thinning of the GBM can cause transient nephrotic-range proteinuria, particularly in the early stages of TBMN.

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Nephrogenetics and Nephrodiagnostics

Deltas

2018

Integration of Omics Approaches and Systems Biology for Clinical Applications

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

Abstract: Our results offer more evidence that in patients with FH, NPHS2-R229Q predisposes to proteinuria and ESKD. R229Q may be a good prognostic marker for young hematuric patients.

Cited by 52 publications

References 15 publications

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

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

Nephrotic-range proteinuria in an infant with thin basement membrane nephropathy

Nephrogenetics and Nephrodiagnostics

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