<i>NPHS2</i>Mutations in Steroid-Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum

Bouchireb, Karim; Boyer, Olivia; Gribouval, Olivier; Névo, Fabien; Huynh-Cong, Evelyne; Morinière, Vincent; Campait, R.; Ars, Elisabet; Brackman, Damien; Dantal, Jacques; Eckart, P.; Gigante, Maddalena; Lipska, Beata S.; Liutkus, Aurélia; Mégarbané, André; Mohsin, Nabil; Özaltın, Fatih; Saleem, Moin A.; Schaefer, Franz; Soulami, Kenza; Torra, Roser; Garcelon, Nicolas; Mollet, Géraldine; Dahan, Karin; Antignac, Corinne

doi:10.1002/humu.22485

Cited by 83 publications

(58 citation statements)

References 79 publications

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“…For instance, we have shown that whereas single-gene causes of SRNS were previously found in 26% of SRNS cases, 2 they were never detected in 120 cases with SSNS, 5 strongly suggesting that individuals with single-gene causes of SRNS will not respond to steroid treatment. 29 This finding has since been confirmed by another group 27 and was again confirmed for 185 individuals with SSNS in this study. Identification of the causative mutation may reveal that a potential therapy is available for some rare singlegene causes of SRNS.…”

Section: Discussionsupporting

confidence: 86%

“…The previously published founder alleles for NPHS2: Arg138Gln (European founder), 11 Pro118Leu (Turkish founder), 12 Val180Met (North African founder), 11 p.Arg138* (Israeli/ Arab founder), 11 Gly140Aspfs*41 (Southern European founder) 11 and Val260Glu (Comoros and the Sultanate of Oman founder) 12 were confirmed in our cohort as predominant in their regions of origin (Supplemental Figure 7). 27 We Figure 7). These findings will help establish genotypephenotype correlations in clinical settings of distinct locations around the world.…”

Section: Allelic Distribution In the 8 Largest Centersmentioning

confidence: 95%

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A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

Sadowski

Lovric

Ashraf

et al. 2015

Journal of the American Society of Nephrology

557

642

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Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of ESRD in the first two decades of life. Effective treatment is lacking. First insights into disease mechanisms came from identification of single-gene causes of SRNS. However, the frequency of single-gene causation and its age distribution in large cohorts are unknown. We performed exon sequencing of NPHS2 and WT1 for 1783 unrelated, international families with SRNS. We then examined all patients by microfluidic multiplex PCR and next-generation sequencing for all 27 genes known to cause SRNS if mutated. We detected a single-gene cause in 29.5% (526 of 1783) of families with SRNS that manifested before 25 years of age. The fraction of families in whom a single-gene cause was identified inversely correlated with age of onset. Within clinically relevant age groups, the fraction of families with detection of the single-gene cause was as follows: onset in the first 3 months of life (69.4%), between 4 and 12 months old (49.7%), between 1 and 6 years old (25.3%), between 7 and 12 years old (17.8%), and between 13 and 18 years old (10.8%). For PLCE1, specific mutations correlated with age of onset. Notably, 1% of individuals carried mutations in genes that function within the coenzyme Q 10 biosynthesis pathway, suggesting that SRNS may be treatable in these individuals. Our study results should facilitate molecular genetic diagnostics of SRNS, etiologic classification for therapeutic studies, generation of genotype-phenotype correlations, and the identification of individuals in whom a targeted treatment for SRNS may be available.

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Section: Discussionsupporting

confidence: 86%

Section: Allelic Distribution In the 8 Largest Centersmentioning

confidence: 95%

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

Sadowski

Lovric

Ashraf

et al. 2015

Journal of the American Society of Nephrology

557

642

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“…Crumbs homolog 2 (CRB2) defects have been associated with steroid-resistant NS. NPHS2 mutations have been associated with steroid resistance (17, 18). …”

Section: Pathology Of Common Causes Of Ns In Childhoodmentioning

confidence: 99%

Pathology of Podocytopathies Causing Nephrotic Syndrome in Children

Ranganathan

2016

Front. Pediatr.

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Nephrotic syndrome (NS) in children includes a diverse group of diseases that range from genetic diseases without any immunological defects to causes that are primarily due to immunological effects. Recent advances in molecular and genomic studies have resulted in a plethora of genetic defects that have been localized to the podocyte, the basic structure that is instrumental in normal filtration process. Although the disease can manifest from birth and into adulthood, the primary focus of this review would be to describe the novel genes and pathology of primary podocyte defects that cause NS in children. This review will restrict itself to the pathology of congenital NS, minimal change disease (MCD), and its variants and focal segmental glomerulosclerosis (FSGS). The two major types of congenital NS are Finnish type characterized by dilated sausage shaped tubules morphologically and diffuse mesangial sclerosis characterized by glomerulosclerosis. MCD has usually normal appearing biopsy features on light microscopy and needs electron microscopy for diagnosis, whereas FSGS in contrast has classic segmental sclerosing lesions identified in different portions of the glomeruli and tubular atrophy. This review summarizes the pathological characteristics of these conditions and also delves into the various genetic defects that have been described as the cause of these primary podocytopathies. Other secondary causes of NS in children, such as membranoproliferative and membranous glomerulonephritis, will not be covered in this review.

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“…Pathogenic podocin mutations are responsible for the steroid-resistant nephrotic syndrome (SRNS-OMIM: 600995), which follows the autosomal recessive mode of inheritance. Podocin is a membrane-integral protein belonging to the stomatin family, and in the kidney it is exclusively localized at the cytoplasmic face of the SD, which bridges podocyte foot processes [19,20,21]. Saleem et al [22 ]showed that it co-localizes with nephrin and cytoskeletal actin while they provided evidence for its role in the foot process formation.…”

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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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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NPHS2Mutations in Steroid-Resistant Nephrotic Syndrome: A Mutation Update and the Associated Phenotypic Spectrum

Cited by 83 publications

References 79 publications

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome

Pathology of Podocytopathies Causing Nephrotic Syndrome in Children

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

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