Alternative titles; symbols
SNOMEDCT: 1260194003; ORPHA: 656; DO: 0080379;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q25.2 | Nephrotic syndrome, type 2 | 600995 | Autosomal recessive | 3 | PDCN | 604766 |
A number sign (#) is used with this entry because of evidence that this form of hereditary renal disease, referred to here as nephrotic syndrome type 2 (NPHS2), can be caused by homozygous or compound heterozygous mutation in the gene encoding podocin (NPHS2; 604766) on chromosome 1q25.
Steroid-resistant nephrotic syndrome type 2 is an autosomal recessive disorder characterized clinically by childhood onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. The disorder is resistant to steroid treatment and progresses to end-stage renal failure in the first or second decades (summary by Fuchshuber et al., 1996). Some patients show later onset of the disorder (Tsukaguchi et al., 2002).
For a general phenotypic description and a discussion of genetic heterogeneity of nephrotic syndrome and FSGS, see NPHS1 (256300).
Naruse et al. (1980) reported 2 sons, of first-cousin parents, who developed the nephrotic syndrome at ages 14 and 15 years. The disorder was resistant to treatment with corticosteroid. Both had progressive renal failure, and renal biopsy in one showed focal glomerulosclerosis. Schwarz et al. (1976) reported 3 sibs with nephrotic syndrome and focal glomerular sclerosis.
Fuchshuber et al. (1995) reported 8 families with childhood-onset steroid-resistant nephrotic syndrome. The age at onset ranged from 3 months to 5 years, and there was rapid progression to end-stage renal failure before age 10. These patients had no disease recurrence after transplantation. Renal biopsy showed focal segmental glomerulosclerosis in 18 cases and minimal-change disease in 2 cases.
Fuchshuber et al. (1996) reported a consanguineous Libyan family with steroid-resistant nephrotic syndrome. The disorder was diagnosed in 4 sibs at the ages of 15, 13, 8, and 9 years; renal biopsy taken in 3 of the 4 showed mesangial proliferation with focal and segmental glomerulosclerosis. A fifth sib, who was apparently healthy at 18 months of age, was found to have haplotypes identical to the 4 affected sibs; reexamination revealed mild proteinuria and mild mesangial hypercellularity with IgM deposits on renal biopsy.
Caridi et al. (2003) identified homozygous or compound heterozygous mutations in the NPHS2 gene in 14 (12%) of 120 patients with steroid-resistant nephrotic syndrome. The age at onset of proteinuria ranged from 1 to 100 months, and all showed progressive renal failure. Histologic findings were consistent with focal segmental glomerulosclerosis in most patients, although minimal-change disease and mesangial proliferation with IgM deposits were rarely observed. Most required renal transplantation; 2 had recurrence of disease after transplantation.
Becker-Cohen et al. (2007) reported an Arab girl, born of distantly related parents, with NPHS2 confirmed by genetic analysis (R138X; 604766.0002). Prenatal ultrasound suggested hyperechoic kidneys, but amniotic fluid was normal. She was found to have nephrotic syndrome at age 2 months. Initial kidney biopsy was normal, but a repeat biopsy performed at 1 year of age showed diffuse mesangial proliferation with segmental sclerosis in 7 glomeruli. Electron microscopy showed diffuse effacement of podocyte foot processes. She later developed edema and her renal function gradually deteriorated, leading to chronic hemodialysis at age 2.5 years. Six months later she received a deceased donor renal transplant, which was complicated by recurrence of nephrotic syndrome 4 years after transplant.
Clinical Variability
Tsukaguchi et al. (2000) reported a 3-generation Brazilian family in which 7 of 10 sibs had late-onset marked proteinuria (all patients), focal segmental glomerulosclerosis (2 patients), or end-stage renal failure requiring kidney transplant (2 patients). The average age of disease onset was 26 years, and the pedigree pattern was consistent with autosomal recessive inheritance. Linkage analysis showed linkage to chromosome 1q25-q31. The phenotype could be distinguished from that described by Fuchshuber et al. (1995) by the later age at onset and the fact that not all patients developed frank nephrotic syndrome. Tsukaguchi et al. (2000) identified affected individuals from 5 additional families with a similar phenotype: the mean age of onset was 21 (range 9 to 31) and 70% of affected individuals progressed to end-stage renal disease. Pathology showed FSGS.
Caridi et al. (2003) identified a heterozygous mutation in the NPHS2 gene in 8 children with proteinuria, including 5 who had a partially steroid-responsive form of the disorder and a slightly milder phenotype. However, the authors could not exclude a second pathogenic mutation in these patients.
Tejani et al. (1983) reported 3 unrelated Hispanic families with the nephrotic syndrome. The histologic lesion in the involved children was either focal segmental glomerulosclerosis or IgM nephropathy evolving into focal sclerosis. Tissue typing revealed the presence of HLA DRw8 in 6 of 8 patients. The study suggested that there may be a genetic predilection towards developing focal segmental glomerulosclerosis.
The occurrence of NPHS2 in sibs and the high incidence of inbreeding in the families reported by Fuchshuber et al. (1995) indicated autosomal recessive inheritance.
Becker-Cohen et al. (2007) reported a 9-year-old Arab girl with NPHS2 due to a homozygous R138X mutation (604766.0002). She presented with recurrent nephrotic syndrome 4 years after renal transplantation from a deceased donor and was treated with plasmapheresis with a partial response. However, renal histology did not demonstrate glomerular immunoglobulin deposition, and an extensive search for anti-podocin antibodies based on indirect Western blot was negative. The findings confirmed the possibility of posttransplantation nephrotic syndrome in patients with NPHS2 mutations, but the lack of immunoglobulin deposition and anti-podocin antibodies implicated another pathogenic mechanism for disease recurrence.
By whole-genome linkage analysis in 9 multiplex families of northern European or northern African origin with childhood-onset nephrotic syndrome, Fuchshuber et al. (1995) assigned the disease locus, symbolized SRN1 by them, to a defined chromosomal region on 1q25-q31. Exclusion of linkage to this region in 1 family proved genetic heterogeneity.
Fuchshuber et al. (1996) performed segregation analysis in a second-degree consanguineous Libyan family with steroid-resistant idiopathic nephrotic syndrome and found linkage to the SRN1 locus on chromosome 1 with a maximum lod score of 3.51 at D1S2883.
By linkage analysis, Boute et al. (2000) refined the localization of the locus identified by Fuchshuber et al. (1996) to a 2.5-megabase region between D1S1640 and D1S3759.
By linkage analysis of a large Brazilian family with adolescent/adult onset of FSGS and proteinuria, Tsukaguchi et al. (2000) found linkage to a locus on chromosome 1q25-31 (maximum 2-point lod score of 3.98 at D1S254 and D1S222). Four of 5 additional families with a similar phenotype showed linkage to the same region. Haplotype analysis delineated a 19-cM region flanked by D1S416 and D1S413. There was overlap with SRN1, suggesting that these clinical subsets of kidney disease may be allelic. Tsukaguchi et al. (2000) noted that since the presentation of FSGS may be subtle, inherited FSGS may be much more common than generally realized and underestimated because of the absence of clear familial patterns.
In 14 of 16 families with steroid-resistant nephrotic syndrome mapping to chromosome 1, 10 of which were previously reported (Fuchshuber et al., 1995; Fuchshuber et al., 1996), Boute et al. (2000) identified 10 different NPHS2 mutations (604766.0001-604766.0010), comprising nonsense, frameshift, and missense mutations, segregating with the disease. One mutation (R138Q; 604766.0001) was found in approximately one-third of the patients.
Caridi et al. (2001) identified homozygous or compound heterozygous mutations in the NPHS2 gene (see, e.g., 604766.0001 and 604766.0004) in 9 of 44 Italian patients with sporadic occurrence of early-onset nephrotic syndrome with focal segmental glomerulosclerosis. All had early onset of proteinuria in childhood and progressed to renal failure necessitating renal transplant. They were not responsive to steroid treatment.
Susceptibility to NPHS2
Tsukaguchi et al. (2002) identified a polymorphism in the NPHS2 gene (R229Q; 604766.0011) that contributed to the development of late-onset renal disease characterized by proteinuria and focal segmental glomerulosclerosis in 6 families. In vitro functional expression assays indicated that the R229Q mutant protein had decreased binding to nephrin (NPHS1; 602716) (41.5% compared to wildtype), suggesting mild functional impairment. Tsukaguchi et al. (2002) concluded that the R229Q variant itself may not cause disease, but appeared to increase susceptibility to renal disease when combined with another pathogenic NPHS2 mutation.
In 7 (18%) of 38 Hungarian patients with childhood-onset nephrotic-range proteinuria, Kerti et al. (2013) identified biallelic mutations in the NPHS2 gene (604766). Three patients had the R138Q mutation on 1 allele and a truncating mutation on the second allele, 1 patient was homozygous for the R138Q mutation, and 1 patient had 2 truncating mutations. All 5 of these patients had the classic phenotype, with onset of the disorder in early childhood and progression to end-stage renal disease in 4 patients by age 10 years. Two individuals with proteinuria only and normal renal function at ages 18 and 31 years, respectively, carried a V290M substitution (604766.0012). The first was homozygous for V290M and the second was compound heterozygous for V290M and R138Q. A third patient with more classic severe NPHS2 resulting in end-stage renal disease at age 8 years carried the V290M variant in the heterozygous state; a second mutation was presumably present but not detected. The V290M variant was not found in 83 French patients with late-onset nephrotic syndrome. However, 2 (1.1%) of 95 European patients with late-onset nephrotic syndrome carried V290M: a German individual carried V290M in compound heterozygosity with a splice site mutation, and a Turkish patient was heterozygous for V290M. Haplotype analysis suggested a founder effect for V290M. Functional studies of the variant were not performed. Kerti et al. (2013) suggested that screening for the V290M mutation should be included for patients with late-onset nephrotic syndrome.
Tory et al. (2014) presented evidence that the R229Q variant (604766.0011) is pathogenic only when combined with a particular type of NPHS2 mutation on the other allele. Among 129 unaffected parents of patients with nephrotic syndrome-2, 6 (4.7%) were found to be compound heterozygous for R229Q on 1 allele and R138Q (604766.0001), R138X (604776.0002), R168H, c.534+1G-T, or R238S on the other allele. These findings clearly demonstrated incomplete penetrance of nephrotic syndrome in individuals with a certain genotype R229Q/mut, when the second mutation occurs in exons 1 to 6 of the NPHS2 gene. In a retrospective analysis of 318 families with NPHS2, there were significantly more patients who were compound heterozygous for R229Q and a mutation affecting exons 7 and 8 of the NPHS2 gene (see, e.g., R291W; 604766.0010) compared to patients who were compound heterozygous for R229Q and a mutation in exons 1 to 6 of the NPHS2 gene (p = 1.2 x 10(-35)). Missense mutations affecting residues ala284, ala288, arg291, ala297, glu310, leu327, or gln328 were enriched in cases with the R229Q mutation. All of these associated mutations in exons 7 and 8 were 3-prime terminal mutations. Transfection studies in human podocyte cell lines showed that the R229Q variant protein localized properly to the plasma membrane when coexpressed with wildtype or variants affecting exons 1 to 6 (R238S or V290M). However, the R229Q protein was retained in the cytoplasm when coexpressed with mutations affecting exons 7 and 8. These interactions mimicked a dominant-negative effect of these mutations on the R229Q variant protein. Structural modeling showed that the combination of R229Q and the pathogenic variants leads to an altered mode of dimerization that likely contributes to the retention of R229Q podocin within cytoplasmic compartments. Tory et al. (2014) noted that these findings have implications for genetic counseling, since the transmission pattern of the disorder may be mutation-dependent.
NPHS2 is the most common known form of inherited steroid-resistant nephrotic syndrome, accounting for 45 to 55% of familial forms and 8 to 20% of sporadic disease (Caridi et al., 2010).
In the literature, the clinical term 'nephrotic syndrome' (NPHS) and the pathologic term 'focal segmental glomerulosclerosis' (FSGS) have often been used to refer to the same disease entity. In OMIM, these disorders are classified as NPHS or FSGS according to how they were first designated in the literature.
Becker-Cohen, R., Bruschi, M., Rinat, C., Feinstein, S., Zennaro, C., Ghiggeri, G. M., Frishberg, Y. Recurrent nephrotic syndrome in homozygous truncating NPHS2 mutation is not due to anti-podocin antibodies. Am. J. Transplant. 7: 256-260, 2007. [PubMed: 17109732] [Full Text: https://doi.org/10.1111/j.1600-6143.2006.01605.x]
Boute, N., Gribouval, O., Roselli, S., Benessy, F., Lee, H., Fuchshuber, A., Dahan, K., Gubler, M.-C., Niaudet, P., Antignac, C. NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nature Genet. 24: 349-354, 2000. Note: Erratum: Nature Genet. 25: 125 only, 2000. [PubMed: 10742096] [Full Text: https://doi.org/10.1038/74166]
Caridi, G., Bertelli, R., Carrea, A., Di Duca, M., Catarsi, P., Artero, M., Carraro, M., Zennaro, C., Candiano, G., Musante, L., Seri, M., Ginevri, F., Perfumo, F., Ghiggeri, G. M. Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J. Am. Soc. Nephrol. 12: 2742-2746, 2001. [PubMed: 11729243] [Full Text: https://doi.org/10.1681/ASN.V12122742]
Caridi, G., Bertelli, R., Di Duca, M., Dagnino, M., Emma, F., Onetti Muda, A., Scolari, F., Miglietti, N., Mazzucco, G., Murer, L, Carrea, A., Massella, L., Rizzoni, G., Perfumo, F., Ghiggeri, G. M. Broadening the spectrum of diseases related to podocin mutations. J. Am. Soc. Nephrol. 14: 1278-1286, 2003. [PubMed: 12707396] [Full Text: https://doi.org/10.1097/01.asn.0000060578.79050.e0]
Caridi, G., Trivelli, A., Sanna-Cherchi, S., Perfumo, F., Ghiggeri, G. M. Familial forms of nephrotic syndrome. Pediat. Nephrol. 25: 241-252, 2010. [PubMed: 19066979] [Full Text: https://doi.org/10.1007/s00467-008-1051-3]
Fuchshuber, A., Janssen, F., Gribouval, O., Niaudet, P., Kamoun, A., Antignac, C. Presymptomatic diagnosis of familial steroid-resistant nephrotic syndrome. (Letter) Lancet 347: 1050-1051, 1996. [PubMed: 8606597] [Full Text: https://doi.org/10.1016/s0140-6736(96)90193-2]
Fuchshuber, A., Jean, G., Gribouval, O., Gubler, M.-C., Broyer, M., Beckmann, J. S., Niaudet, P., Antignac, C. Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum. Molec. Genet. 4: 2155-2158, 1995. [PubMed: 8589695] [Full Text: https://doi.org/10.1093/hmg/4.11.2155]
Kerti, A., Csohany, R., Szabo, A., Arkossy, O., Sallay, P., Moriniere, V., Vega-Warner, V., Nyiro, G., Lakatos, O., Szabo, T., Lipska, B. S., Schaefer, F., Antignac, C., Reusz, G., Tulassay, T., Tory, K. NPHS2 p.V290M mutation in late-onset steroid-resistant nephrotic syndrome. Pediat. Nephrol. 28: 751-757, 2013. [PubMed: 23242530] [Full Text: https://doi.org/10.1007/s00467-012-2379-2]
Naruse, T., Hirokawa, N., Maekawa, T., Azato, H., Ito, K., Kaya, H. Familial nephrotic syndrome with focal glomerular sclerosis. Am. J. Med. Sci. 280: 109-113, 1980. [PubMed: 7001902] [Full Text: https://doi.org/10.1097/00000441-198009000-00007]
Schwarz, R., Stogmann, W., Fischbach, H. Familiaeres nephritisches Syndrom mit fokaler Glomerulosklerose. Wien. Klin. Wschr. 88: 548-554, 1976. [PubMed: 997538]
Tejani, A., Nicastri, A., Phadke, K., Sen, D., Adamson, O., Dunn, I., Calderon, P. Familial focal segmental glomerulosclerosis. Int. J. Pediat. Nephrol. 4: 231-234, 1983. [PubMed: 6229501]
Tory, K., Menyhard, D. K., Woerner, S., Nevo, F., Gribouval, O., Kerti, A., Straner, P., Arrondel, C., Cong, E. H., Tulassay, T., Mollet, G., Perczel, A., Antignac, C. Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nature Genet. 46: 299-304, 2014. [PubMed: 24509478] [Full Text: https://doi.org/10.1038/ng.2898]
Tsukaguchi, H., Sudhakar, A., Le, T. C., Nguyen, T., Yao, J., Schwimmer, J. A., Schachter, A. D., Poch, E., Abreu, P. F., Appel, G. B., Pereira, A. B., Kalluri, R., Pollak, M. R. NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J. Clin. Invest. 110: 1659-1666, 2002. [PubMed: 12464671] [Full Text: https://doi.org/10.1172/JCI16242]
Tsukaguchi, H., Yager, H., Dawborn, J., Jost, L., Cohlmia, J., Abreu, P. F., Pereira, A. B., Pollak, M. R. A locus for adolescent and adult onset familial focal segmental glomerulosclerosis on chromosome 1q25-31. J. Am. Soc. Nephrol. 11: 1674-1680, 2000. [PubMed: 10966492] [Full Text: https://doi.org/10.1681/ASN.V1191674]