Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations

Benoît, Geneviève; Machuca, Eduardo; Antignac, Corinne

doi:10.1007/s00467-010-1495-0

Cited by 155 publications

(151 citation statements)

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“…However, the NPHS1 mutation detection rate remains high amongst non-Finnish cases of CNS [8,10,65]. Mutations in the NPHS2 gene, encoding podocin, are also responsible for a significant number of CNS cases, and the phenotype varies from the severe CNF presentation to milder disease with onset of proteinuria occurring later than in those with NPHS1 mutations [4,66,67]. Mutations in the PLCE1, WT1 and LAMB2 genes have also been detected in patients presenting with isolated CNS; mutations in these genes will be discussed in more detail in the next section.…”

Section: Congenital Nsmentioning

confidence: 99%

“…Classification is based on the response to treatment with glucocorticoids (Gc) as either steroid-sensitive (where Gc induces remission) or steroid-resistant NS (SRNS). Approximately 80% of paediatric NS cases respond to Gc, with the remaining 20% being steroid-resistant [4]. SRNS may be further characterised by renal histology, with the majority of cases showing focal segmental glomerulosclerosis (FSGS) [5] and, to a lesser extent, minimal change disease (MCD) or diffuse mesangial sclerosis (DMS).…”

Section: Introductionmentioning

confidence: 99%

“…There is significant heterogeneity in the onset and clinical course of SRNS, and neither the clinical features nor the histological pattern predicts therapy response. However, SRNS is more likely to show resistance to a range of immunosuppressive agents [6] and progress to end-stage renal disease (ESRD) at a faster rate [4,7].…”

Section: Introductionmentioning

confidence: 99%

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Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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Steroid-resistant nephrotic syndrome (SRNS) is a common cause of chronic kidney disease in childhood and has a significant risk of rapid progression to end-stage renal disease. The identification of over 50 monogenic causes of SRNS has revealed dysfunction in podocyte-associated proteins in the pathogenesis of proteinuria, highlighting their essential role in glomerular function. Recent technological advances in high-throughput sequencing have enabled indication-driven genetic panel testing for patients with SRNS. The availability of genetic testing, combined with the significant phenotypic variability of monogenic SRNS, poses unique challenges for clinicians when directing genetic testing. This highlights the need for clear clinical guidelines that provide a systematic approach for mutational screening in SRNS. The likelihood of identifying a causative mutation is inversely related to age at disease onset and is increased with a positive family history or the presence of extra-renal manifestations. An unequivocal molecular diagnosis could allow for a personalised treatment approach with weaning of immunosuppressive therapy, avoidance of renal biopsy and provision of accurate, well-informed genetic counselling. Identification of novel causative mutations will continue to unravel the pathogenic mechanisms of glomerular disease and provide new insights into podocyte biology and glomerular function.

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Section: Congenital Nsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

2017

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“…Mutations in more than 20 genes have been identified in monogenic forms of SRNS, most of which encode podocyte proteins3-5. NPHS2, encoding podocin, is the most frequently mutated of these genes and is responsible for 12-18% of SRNS cases 3,6,7 . Podocin accumulates in dimeric or oligomeric forms in lipid raft microdomains at the podocyte slit diaphragm, which is the key component of the glomerular filtration barrier.…”

mentioning

confidence: 99%

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

et al. 2014

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Abbreviations: NPHS2: nephrosis 2, steroid-resistant ; SRNS: steroid-resistant nephrotic syndrome Introductory paragraphNephrotic syndrome is the consequence of damage to the glomerular filtration barrier, and it refers to the clinical symptoms of heavy proteinuria, hypoalbuminemia, edema and hyperlipidemia. The steroidresistant form of nephrotic syndrome (SRNS) has a poor prognosis, as it often leads to endstage renal disease (ESRD) 1,2 . Mutations in more than 20 genes have been identified in monogenic forms of SRNS, most of which encode podocyte proteins3-5. NPHS2, encoding podocin, is the most frequently mutated of these genes and is responsible for 12-18% of SRNS cases 3,6,7 . Podocin accumulates in dimeric or oligomeric forms in lipid raft microdomains at the podocyte slit diaphragm, which is the key component of the glomerular filtration barrier. On the basis of its predicted structure, podocin belongs to the stomatin protein family, with a hairpin-like intramembrane loop and intracellular N and C termini. The C-terminal portions of both stomatin and podocin are responsible for dimerization 6,[8][9][10][11][12] .Individuals with NPHS2 mutations typically develop SRNS before 6 years of age and progress to ESRD during their first decade of life6. The phenotype can be less severe in the setting of a trans association of an NPHS2 mutation and the polymorphism c.686G>A (p.Arg229Gln, rs61747728), a genotype we hereafter denote as p.[Arg229Gln];[mut] that causes SRNS with a median age at diagnosis of 13 years (range, 0-39 years) and progression to ESRD by 26 years (range, 10-50 years) 7,[13][14][15][16][17][18] . Nevertheless, the p.Arg229Gln variant in the homozygous state does not cause SRNS 19,20 .On the basis of the 15× higher allele frequency of p.Arg229Gln (357/13,006, 2.7%) than the cumulative allele frequency of the known disease-causing variants 13-18,21-43 (24/13,006, 0.18%)

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“…However, after 8 weeks of oral prednisone treatment, complete remission was achieved. It is possible that a subset of SRNS with a response to immunosuppressive agents has an underlying immune defect (Benoit et al, 2010). Therefore, we do not consider IVS4+14T>C to be a causative mutation of SRNS.…”

Section: Discussionmentioning

confidence: 99%

Mutations in WT1 in boys with sporadic isolated steroid-resistant nephrotic syndrome

Yang¹,

Zhao²,

Tu³

et al. 2016

Genet. Mol. Res.

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ABSTRACT. Mutations in the Wilms' tumor gene, WT1, can lead to syndromic steroid-resistant nephrotic syndrome and isolated steroidresistant nephrotic syndrome. WT1 mutations have been identified in the majority of children with Denys-Drash or Frasier syndrome. WT1 mutations have not previously been identified in boys with sporadic isolated steroidresistant nephrotic syndrome, but, recently, four boys with isolated nephrotic syndrome were identified to have WT1 mutations. However, whether boys with sporadic isolated steroid-resistant nephrotic syndrome should be routinely subjected to mutation analysis of WT1 has not been established. We examined 35 boys with sporadic isolated steroid-resistant nephrotic syndrome for mutations in WT1. Mutation analysis of all 10 exons of WT1 was performed by polymerase chain reaction and direct sequencing. all 35 patients. No causative WT1 mutation was identified in any of the patients. The WT1 mutation, IVS4+14T>C, which is not predicted to affect splicing, was identified in one patient who achieved complete remission after 8 weeks of oral prednisone treatment, indicating that IVS4+14T>C is not a causative mutation. Five WT1 polymorphisms were also identified in some patients and controls. Our results suggest that mutation analysis of WT1 should not be routinely performed for genetically defined boys with sporadic isolated steroid-resistant nephrotic syndrome.

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Hereditary nephrotic syndrome: a systematic approach for genetic testing and a review of associated podocyte gene mutations

Cited by 155 publications

References 100 publications

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Genetic testing in steroid-resistant nephrotic syndrome: why, who, when and how?

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

Mutations in WT1 in boys with sporadic isolated steroid-resistant nephrotic syndrome

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