NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele

Tsukaguchi, Hiroyasu; Sudhakar, Akulapalli; Le, Tu C.; Nguyen, Trang Thu; Yao, Jun; Schwimmer, Joshua A.; Schachter, Asher D.; Poch, Esteban; Abreu, Patrícia Ferreira; Appel, Gerald B.; Pereira, Aparecido B.; Kalluri, Raghu; Pollak, Martin R.

doi:10.1172/jci0216242

Cited by 190 publications

(156 citation statements)

References 31 publications

(38 reference statements)

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“…Interestingly, the alpha actinin 4 mRNA is underexpressed in the glomeruli of patients with microalbuminuria compared with patients with normal AER [10]. In addition, a combination of glucose and advanced glycation end-products reduced the expression of alpha actinin-4 at both the protein and the Table 1 c Patients homozygous for the minor allele (2/2) were compared with patients homozygous for the major allele (1/1) d The non-synonymous R229Q SNP in NPHS2 characterised by Tsukaguchi et al [13] was included mRNA level in podocytes in vitro [11]. Whether or not the observed variation in ACTN4 represents a true association remains to be determined in replication studies in other populations.…”

Section: Discussionmentioning

confidence: 99%

Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy

et al. 2007

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Aims/hypothesis The slit diaphragm is an adhesion and signalling protein complex linking the interdigitating podocyte foot processes in the kidney glomerulus, and mutations in slit diaphragm-associated genes result in severe proteinuria. Here we report a genetic association analysis of four slit diaphragm genes, LRRC7, KIRREL, NPHS2 and ACTN4, in a Finnish diabetic nephropathy cohort. Materials and methods A total of 40 single nucleotide polymorphisms (SNPs) were genotyped in 1103 patients with type 1 diabetes. The patients were classified according to their renal status, and the genotype data were analysed in a cross-sectional case-control setting. To confirm positive associations, four SNPs were genotyped in 1,025 additional patients with type 1 diabetes. Results No associations with diabetic nephropathy were observed for any of the analysed SNPs. The SNPs were not associated with the time from the onset of diabetes to the diagnosis of nephropathy or with glomerular filtration rate or AER as quantitative variables. In a sex-specific sub-analysis, the variants rs979972 and rs749701 in the first intron of ACTN4 were nominally associated with diabetic nephropathy in females, with odds ratios of 1.81 (95% CI 1.18-2.79, p=0.007) and 1.93 (95% CI 1.26-2.96, p=0.003) respectively. Conclusions/interpretation Our study has not found any evidence that common variants in LRRC7, KIRREL, NPHS2 and ACTN4 contribute to susceptibility to diabetic nephropathy in Finnish patients with type 1 diabetes.

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Section: Discussionmentioning

confidence: 99%

Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy

et al. 2007

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“…[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 .…”

Section: Introductory Paragraphmentioning

confidence: 99%

“…Nevertheless, the high allele frequency of p.Arg229Gln in late onset SRNS (5.7-7.5%) [16][17][18] points to its pathogenicity in some cases. Recognizing that this discrepancy could reflect the influence of the trans-associated mutations, we compared the exonic localization of the mutations between cases with [mut]; [mut] and cases with p.…”

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confidence: 99%

“…[Arg229Gln]; [mut] in 318 families from French and other SRNS cohorts [13][14][15][16][17][18] and found a striking difference (P = 1.2 × 10−35; Table 1). Notably, whereas mutations in the last two exons (7 and 8) were rare in cases with [ Out of the 56 mutations located in exons 1-6, only 4 were associated with p.Arg229Gln in cases with SRNS, and these accounted for only 8 of 71 (11%) total p.Arg229Gln-associated alleles (Tables 1 and 2) Table 2).…”

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confidence: 99%

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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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“…3-9 The polymorphism R229Q is one of the most commonly reported podocin sequence variations, and has repeatedly been found with slightly increased frequency in SRNS and FSGS cases compared to healthy controls. 5,8,10 The arginine (R) residue at protein position 229 is highly conserved across species, and the arginine-toglutamine substitution R229Q (p.229Arg>Glu, corresponding to the nucleotide substitution g. 686G>A) has been reported to alter functional properties of podocin in vitro 5 and possibly in vivo. 11…”

Section: Introductionmentioning

confidence: 99%

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

Köttgen

Hsu

Coresh

et al. 2008

American Journal of Kidney Diseases

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Background-Rare mutations in nephrosis 2 (NPHS2), encoding podocin, are found in patients with familial and sporadic steroid resistant nephrotic syndrome and focal segmental glomerular sclerosis. The objective of this study was to assess the contribution of the commonly reported functional podocin polymorphism R229Q to kidney disease in the population-at-large and to replicate a prior study of an association of R229Q and albuminuria in the general population.

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NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele

Cited by 190 publications

References 31 publications

Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy

Association analysis of podocyte slit diaphragm genes as candidates for diabetic nephropathy

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

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

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