The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy

Tonna, Stephen; Wang, Yan Yan; Wilson, D.; Rigby, Lin; Tabone, Tania; Cotton, Richard G.H.; Savige, Judy

doi:10.1007/s00467-008-0934-7

Cited by 50 publications

(40 citation statements)

References 30 publications

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“…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%

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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%

“…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%

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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“…In conclusion, the implication that variant R229Q in the podocin protein may predispose to proteinuria in TBMN [12] is somewhat premature and needs further experimentation. It is equally important either to confirm this association or to reject it; however, it is of paramount importance for us to identify the factor or factors that clearly predispose a subgroup of TBMN patients to proteinuria, or even FSGS and renal failure, thereby enabling us to identify high-risk patients for early intervention.…”

mentioning

confidence: 97%

“…In a recent publication in this journal Tonna et al [12] reported on 56 TBMN patients (on the basis of persistent hematuria), some of whom also had proteinuria of ≥300 mg/l, or ≥500 mg/l. Among these, 3 of 5 (60%) who carried the R229Q variant of the glomerular filtration barrier protein podocin [encoded by the nephrosis 2 (NPHS2) gene] had proteinuria of ≥500 mg/l, whereas only 7 of 51 (14%) who did not carry R229Q had a similar level of proteinuria.…”

mentioning

confidence: 99%

Thin basement membrane nephropathy: is there genetic predisposition to more severe disease?

Deltas

2009

Pediatr Nephrol

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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: 75%

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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The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy

Cited by 50 publications

References 30 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

Thin basement membrane nephropathy: is there genetic predisposition to more severe disease?

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

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