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CLINICAL SCIENCE |
*Departments of Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan; University Children’s Hospital, Duesseldorf, Germany; University Children’s Hospital, Erlangen, Germany; University Children’s Hospital, Greifswald, Germany; ||Section of Pediatric Nephrology, Department of Pediatrics, University of the Philippines-Philippine General Hospital, Medical Center, Manila, Philippines; ¶University Children’s Hospital, Freiburg, Germany; #University Children’s Hospital, New Delhi, India; **University Children’s Hospital, Zurich, Switzerland; and Hacettepe University School of Medicine, Ankara, Turkey.
Correspondence to Dr. Friedhelm Hildebrandt, University of Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0646. Phone: 734-615-7285; Fax: 734-615-1386; E-mail: fhilde{at}umich.edu
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Introduction |
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-actinin 4 (OMIM no. 604638), have been identified as an autosomal dominant cause of SRNS (11). An additional locus for an autosomal dominant form of NS has been mapped to chromosome 11q21–q22 (OMIM no. 603965) (12). Identification of candidate genes for monogenic forms of SRNS indicates the importance of genetic factors in the pathogenesis of NS. Through identification of these three causative genes for SRNS, their gene products (nephrin, podocin, and -actinin 4) were identified as being important for the function of the glomerular slit membrane of podocyte foot processes, which constitutes the primary molecular sieve of glomeruli (13). Familial SRNS has been described as a childhood onset of proteinuria, rapid progression to ESRD, resistance to standard steroid therapy, and an absence of recurrence after renal transplantation (8). Since the identification of the NPHS2 gene encoding podocin, different groups have demonstrated that mutations in the NPHS2 gene represent a frequent cause of SRNS, occurring in 20 to 30% of sporadic (i.e., nonfamilial) cases of SRNS (14–17). In addition, mutations in the NPHS2 gene were recently identified as a cause of an adult-onset form of FSGS (18). Initial reports suggested that children with NPHS2 mutations might exhibit primary resistance to standard steroid treatment. Those data, however, involved only 14 patients (10). In addition, the risk for FSGS recurrence in the renal transplant seemed to be much lower than the 30% recurrence rate observed in the general FSGS population (19). Again, these findings involved very few patients (10,17).
We therefore sought to examine these potential genotype/phenotype relationships among a large number of patients. Specifically, we performed mutational analysis for all eight NPHS2 exons among 190 patients with SRNS from 165 different families and, as a control sample, 124 patients with SSNS from 120 different families. Our primary goals were to determine, among patients with homozygous or compound heterozygous mutations in NPHS2, (1) whether the patients respond to standard steroid treatment and (2) whether the risk of FSGS recurrence in a kidney transplant is indeed lower than among patients without mutations in NPHS2. We demonstrate that patients with homozygous or compound heterozygous mutations in NPHS2 always exhibited primary steroid resistance and were not observed in the group with SSNS. In addition, we demonstrate that the rate of FSGS recurrence in a renal transplant was only 8% (two of 24 patients) among patients with homozygous or compound heterozygous mutations in NPHS2, compared with 35% (seven of 20 patients) among patients without NPHS2 mutations. Mutational analysis of NPHS2 among patients with SRNS might therefore help direct long-term treatment plans for patients with NPHS2 mutations.
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) and 124 patients (from 120 different families) were initially steroid-sensitive (SSNS) (Table 2). Renal biopsy results for patients with SRNS were as follows: FSGS, 115 of 190 patients (61%); MCNS, 34 of 190 patients (18%); mesangioproliferative glomerulonephritis, five of 190 patients (2%); membranoproliferative glomerulonephritis, four of 190 patients (2%); diffuse mesangial sclerosis, three of 190 patients (1%); IgM nephropathy, one of 190 patients (1%); congenital NS, one of 190 patients (1%); no data or no biopsy performed, 27 of 190 patients (14%) (Tables 1 and 2). Renal biopsy results for patients with SSNS were as follows: FSGS, 26 of 124 patients (21%); MCNS, 22 of 124 patients (18%); membranoproliferative glomerulonephritis, five of 124 patients (4%); mesangioproliferative glomerulonephritis, two of 124 patients (1%); no data or no biopsy performed, 69 of 124 patients (56%) (Table 2). The small number of biopsies performed in SSNS is explained by the milder course of SSNS. The median age of onset was 3.5 yr for the patients with SRNS and 4.4 yr for the patients with SSNS (Table 2). Congenital NS was diagnosed for 21 of 190 patients (11%) with SRNS. The median age of onset of NS for the patients with SRNS was 4.0 yr, after subtraction of the patients with congenital NS (Table 2). Sixty-eight of 190 patients with SRNS (36%) exhibited progression to ESRD, with a median age of 10.1 yr (Table 2). Two of 124 patients with SSNS, from different families, exhibited progression to ESRD. Both patients were initially steroid-sensitive and became steroid-resistant in a later phase of the disease. To strengthen the statistical power of the study, clinical data for 52 different SRNS families that we described previously (14) were included in this study. Data for those families in Table 1 and Figure 1 are specified. Clinical data for those patients were updated where possible.
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). For four of 165 families with SRNS (2%), only a single heterozygous sequence variant was observed, which does not explain the phenotype for a recessive disease and is primarily considered a polymorphism (Tables 1 and 2). Twenty-seven of fifty-six patients with SRNS (48%) with homozygous or compound heterozygous mutations in NPHS2 represented familial cases, whereas 29 of 56 patients (52%) represented sporadic cases. Of the total of 152 patients with sporadic SRNS, 29 (19%) had homozygous or compound heterozygous mutations in NPHS2. In contrast to the findings for SRNS, none of the 120 families with primary SSNS demonstrated homozygous or compound heterozygous mutations in NPHS2 (Table 2). For four of 120 families with SSNS (3%), only a single heterozygous sequence variation in NPHS2 was observed (Tables 1 to 3).
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In particular, the following novel mutations were observed (Figure 1, Table 1). (1) A G304A transition leading to the nonconservative amino acid exchange E102K, conserved in mice during evolution, occurred heterozygously in F1041. (2) A C353T transition leading to the nonconservative amino acid exchange P118L, conserved during evolution in mice, Drosophila melanogaster, and Caenorhabditis elegans, occurred homozygously in F1059 and F1083 and heterozygously in F1028. (3) A G378T transversion leading to the nonconservative amino acid exchange K126N, conserved in mice during evolution, occurred heterozygously in F1221. (4) A G503A transition leading to the conservative amino acid exchange R168H, conserved in mice during evolution, occurred heterozygously in F1006 and F942. (5) A G770A transition leading to the nonconservative amino acid exchange G257E, conserved during evolution in mice, D. melanogaster, and C. elegans, occurred homozygously in F873. (6) A T803G transversion leading to the conservative amino acid exchange V268G, conserved during evolution in mice, D. melanogaster, and C. elegans, occurred homozygously in F1077. (7) An insertion of adenine at position 29 in codon 10, inducing a frameshift and resulting in a stop codon at E69X, occurred heterozygously in F1041. (8) A deletion of thymine at position 948 in codon 346, inducing a frameshift and resulting in a stop codon at L347X, occurred homozygously in F1139 and heterozygously in F861 and F1221. (9) The obligatory splice site mutation IVS3+2T
A, involving the 5' donor splice site of intron 3, occurred heterozygously in F1005. (10) The obligatory splice site mutation IVS7+2TA, involving the 5' donor splice site of intron 7, occurred heterozygously in F888.
Types of Single Heterozygous Sequence Variants/Polymorphisms
In four families with SRNS and four families with SSNS, only a single heterozygous sequence variant/polymorphism was observed (Table 1). All of those single heterozygous sequence variants/polymorphisms were absent from 80 healthy control individuals. In total, six different single heterozygous sequence variants/polymorphisms were observed. Two single heterozygous sequence variants/polymorphisms, G413A (R138Q) and C871T (R291W), occurred in compound heterozygous or homozygous mutations in other families with SRNS (Figure 1, Table 1). Functional data demonstrated the relevance of these nucleotide variants (18,22). Three other single heterozygous sequence variants/polymorphisms, Q328R (F923), A242V (F1104), and E237Q (F1086), were not observed in compound heterozygous or homozygous mutations in other families with SRNS (Figure 1, Table 1). Two of the mutations were novel. (1) A G709C transversion leading to the conservative amino acid exchange E237Q, conserved in mice during evolution, occurred heterozygously in F1086 and F3908. (2) An A983T transversion leading to the nonconservative amino acid exchange Q328R, conserved in mice during evolution, occurred heterozygously in F923. Because no second mutation was observed in the recessive NPHS2 gene, the significance of these single heterozygous sequence variants/polymorphisms for the disease phenotype is unclear. In one family (F4286), the amino acid exchange P20L, which was initially described by Boute et al. (10), was observed as a single heterozygous sequence variant. However, we consider this to represent an innocuous polymorphism, for the following reasons: (1) we observed three heterozygous nucleotide variants (P20L, R138Q, and R168H) in family F1006, (2) P20L occurred homozygously in two healthy control persons, and (3) the position is not conserved during evolution. The common polymorphism R229Q was observed for 13 of 190 patients with SRNS (7%), six of 124 patients with SSNS (6%), and nine of 80 healthy control subjects (11%). No significant difference among those groups could be noted. No other sequence variants affecting the coding protein sequence were detected among the 80 healthy control subjects.
Clinical Data for Patients with Mutations/Sequence Variations in NPHS2
We detected homozygous or compound heterozygous mutations in NPHS2 for 56 of 190 patients with SRNS (29%) and 43 of 165 different families (26%) (Tables 1 and 2). For 14 of 22 patients with congenital NS (64%), homozygous or compound heterozygous mutations in NPHS2 were observed. For seven of 22 patients with congenital NS (32%), homozygous or compound heterozygous mutations in NPHS1 were observed (Ruf et al., unpublished observations). For one patient with congenital NS, no mutation in NPHS2 or NPHS1 was observed. After exclusion of the patients with congenital NS, the median age of onset for patients with homozygous or compound heterozygous mutations in NPHS2 was 3.4 yr (range, 0.3 to 24.0 yr), compared with 5.0 yr (range, 0.0 to 19.0) for the patients without mutations. Data on responses to treatment were available for 29 of 31 patients with SRNS and homozygous or compound heterozygous mutations in NPHS2 who were treated with CsA or CP. None of those 29 patients achieved complete remission; five patients exhibited partial responses. For patients with homozygous or compound heterozygous mutations in NPHS2, the histologic findings from the kidney biopsies were as follows: FSGS, 37 of 56 patients (66%); MCNS, eight of 56 patients (14%); mesangioproliferative glomerulonephritis, two of 56 patients (3%); IgM nephropathy, one of 56 patients (2%); diffuse mesangial sclerosis, one of 56 patients (2%); congenital NS, one of 56 patients (2%); no data or no biopsy performed, six of 56 patients (11%) (Tables 1 and 2 ). For patients without mutations in NPHS2, the histologic findings were as follows: FSGS, 80 of 129 patients (62%); MCNS, 20 of 129 patients (16%); membranoproliferative glomerulonephritis, five of 129 patients (4%); mesangioproliferative glomerulonephritis, three of 129 patients (2%); diffuse mesangial sclerosis, two of 129 patients (2%); no data or no biopsy performed, 19 of 129 patients (14%). Therefore, renal histologic features did not differ for the groups of patients with and without the presence of homozygous or compound heterozygous mutations in NPHS2. Thirty-three of 56 patients with SRNS (59%) with homozygous or compound heterozygous mutations in NPHS2 exhibited progression to ESRD, at a median age of 10.0 yr and at a median time of 6.0 yr (range, 1.5 to 21.2 yr) after the onset of disease symptoms. Thirty-four of 129 patients with SRNS (26%) without mutations in NPHS2 exhibited progression to ESRD, at a median age of 10.5 yr and at a median time of 3.0 yr (range, 1.5 to 19.8 yr) after the onset of symptoms of NS. Kidney transplantation was performed for 24 patients with SRNS with homozygous or compound heterozygous mutations in NPHS2 and for 20 patients without mutations in NPHS2. Seven of 20 patients with SRNS (35%) but without mutations in NPHS2 developed recurrence of FSGS in their renal transplants, which is in accordance with data on FSGS recurrence published before mutational analysis of NPHS2 was possible. In contrast, only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2 developed FSGS recurrence. One of those two patients, F1139, demonstrated progressive proteinuria on day 7 after transplantation, which responded to immunosuppressive therapy. No biopsy was performed, and the function of the transplant is stable after 7 mo (Billing et al., unpublished observations). No histologic evidence of the recurrence of FSGS has been noted to date. For four patients with SSNS (F3147, F3908, F4286, and F1172), a single heterozygous sequence variation in the NPHS2 gene was observed. F3147 and F4286 experienced one episode of NS, which responded to steroid therapy. Biopsy results indicated MCNS for F4286, and no biopsy was performed for F3147. For F3908, two relapses of NS, which responded to steroid treatment, occurred after the initial steroid therapy. Histologic findings revealed MCNS. No clinical follow-up data were available. F1172 became resistant to steroids and CsA after initial steroid responsiveness. The histologic findings for the kidney biopsy indicated FSGS.
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). For none of the 120 SSNS families were homozygous or compound heterozygous mutations in NPHS2 identified. We therefore conclude that patients with homozygous or compound heterozygous mutations in NPHS2 exhibit primary resistance to standard steroid treatment. When familial and sporadic cases of SRNS were considered together, we observed homozygous or compound heterozygous mutations in NPHS2 for 29% of patients from different families. When 14 familial SRNS cases were excluded from the total of 165, homozygous or compound heterozygous mutations in NPHS2 were observed for 29 of 152 sporadic SRNS cases (19%). Caridi et al. (17) observed homozygous or compound heterozygous mutations in NPHS2 for 14 of 120 patients with SRNS (12%). In contrast to those data, Maruyama et al. (23) performed mutational analysis for 36 Japanese children with SRNS without detecting any mutation in NPHS2. A different genetic background in the Japanese population could explain this finding. Variations in disease incidences among different ethnic groups have been described for other genetic diseases (24).
In contrast to the findings in SRNS, we did not detect any homozygous or compound heterozygous mutations in NPHS2 among 124 patients with SSNS. Caridi et al. (17) performed mutational analysis of NPHS2 for 59 patients with SSNS and Frishberg et al. (25) performed mutational analysis for 15 patients with SSNS without identifying any homozygous or compound heterozygous mutations in NPHS2. These data confirm that patients with homozygous or compound heterozygous mutations in NPHS2 exhibit primary resistance to standard steroid treatment. Because methylprednisolone pulse therapy was not evaluated in this study, no conclusion can be drawn regarding that mode of therapy.
We also provide data on a genotype/phenotype correlation regarding homozygous or compound heterozygous mutations in NPHS2 and the recurrence of FSGS after kidney transplantation. On the basis of a small number of patients (<14 patients) with kidney transplants in the initial identification of the NPHS2 gene (10), it was suspected that FSGS may not recur after kidney transplantation among such patients. No details regarding the number of patients who received kidney transplants were available at that time (10). We demonstrated that, whereas seven of 20 patients with SRNS (35%) without NPHS2 mutations experienced FSGS recurrence in a renal transplant, only two of 24 patients with SRNS (8%) with homozygous or compound heterozygous mutations in NPHS2 exhibited recurrence. Proteinuria was noted for one of the two patients with recurrence, which responded to steroid therapy (Table 2). No histologic evidence of FSGS recurrence has been noted to date. Our data thus demonstrate a significantly reduced risk of FSGS recurrence in a kidney transplant among patients with homozygous or compound heterozygous mutations in NPHS2, compared with patients without such mutations. This finding of a lower recurrence risk among patients with homozygous or compound heterozygous mutations in NPHS2 could help direct the planning of living related donor transplants, which might be considered more readily on the basis of a lower recurrence risk. However, these data are in contrast to those of Bertelli et al. (26), who described FSGS recurrence for five of 12 patients (38%) with mutations in NPHS2 (two of 12 with homozygous or compound heterozygous mutations in NPHS2 and three of 12 patients with single heterozygous sequence variants in one allele of NPHS2) (26). The discrepancy can be explained by noting that (1) the recurrence of FSGS was proven by biopsy for only one of nine patients described by Bertelli et al. (26), whereas the second patient exhibited only a short period of proteinuria, with a prompt response to plasmapheresis, and (2) two patients with SRNS and FSGS recurrence described by Bertelli et al. (26) carried the single heterozygous sequence variant P20L. Our data indicate that this sequence variant most likely represents a polymorphism, because it occurred homozygously in a healthy control subject and the position is not conserved during evolution. Another patient described by Bertelli et al. (26) carried the single heterozygous sequence variant S211T. The functional relevance of this single heterozygous sequence variant remains unclear. Different pathogenic hypotheses have been postulated to explain the recurrence of FSGS. The most popular hypothesis suggests the involvement of one or more circulating factors altering renal permeability to proteins and causing proteinuria (4). Among patients with a molecular defect in both alleles of NPHS2, a defect in the protein podocin is considered to be the disease-causing mechanism. After kidney transplantation, the disease-causing mechanism should be cured. The occurrence of autoantibodies against podocin, as described for congenital NS, could explain the recurrence of disease. However, data reported by Bertelli et al. (26) render this hypothesis unlikely. Although our data indicate a reduced risk after renal transplantation for patients with homozygous or compound heterozygous mutations in NPHS2, recurrence of FSGS cannot be excluded in this population of patients. This indicates a pathogenesis of FSGS involving additional extrarenal mechanisms.
Thirty-one patients with homozygous or compound heterozygous mutations in NPHS2 in our cohort were treated with CsA or CP or both. Data on the results of treatment were available for 29 patients. Complete remission after therapy was observed for none of those patients. No clinical response was observed for 24 patients (83%), and a partial response was noted for five (17%) (Tables 1 and 2). In comparison, 64 patients without mutations in NPHS2 received CsA or CP treatment. Twelve of 64 patients (19%) demonstrated complete remission, 14 of 64 patients (22%) a partial response, and 38 of 64 patients (59%) no response (Table 2). Frishberg et al. (25) reported that several of 13 patients with homozygous or compound heterozygous mutations in NPHS2 did not respond to immunosuppressive therapy, including CsA and CP; no clinical details were provided. Caridi et al. (17) reported on eight patients with homozygous or compound heterozygous mutations in NPHS2 who received treatment with CsA without any response. Our data and the cited data on the responses to CsA and CP therapy among patients with homozygous or compound heterozygous mutations in NPHS2 suggest that the patients with homozygous or compound heterozygous mutations in NPHS2 might exhibit decreased responses to treatment. Different groups discussed an immunopathogenetic hypothesis for the pathogenesis of NS, including speculation regarding a circulating FSGS factor (4–7). This also explains the success of immunosuppressive therapy for NS. As mentioned above, the molecular defect in NPHS2 and the resulting defect in the protein podocin are considered the disease-causing mechanism among patients with mutations in NPHS2. These defects are most likely not changeable with immunosuppressive therapy, as indicated by the nonresponsiveness of these patients to steroid therapy. However, five patients with molecular defects in NPHS2 exhibited partial responses to CsA or CP therapy. These findings indicate a complex pathogenesis of FSGS, involving additional extrarenal mechanisms. The number of patients studied to date regarding responses to CsA or CP treatment is not sufficient to provide a statistically significant result to suggest a change in the therapeutic regimen for SRNS. Therefore, these data should be considered preliminary. Further studies with larger numbers of patients with SRNS will be important to delineate the influence of the presence of homozygous or compound heterozygous mutations in NPHS2 on responses to CsA and CP treatment.
On the basis of the data on the lack of responses to standard steroid therapy among patients with homozygous or compound heterozygous mutations in NPHS2, we propose performing mutational analysis of NPHS2 for every child (if consent can be obtained) immediately after presentation with the first episode of NS. Because the data are still based on a limited variety of ethnic and genetic backgrounds and because performance of the mutational analysis requires approximately 2 to 3 mo (www.renalgenes.org, www.genetests.org), the initial standard steroid therapy should be administered. If the patient is carrying homozygous or compound heterozygous mutations in NPHS2, then a second trial of standard steroid therapy is not justified. It will be important to generate additional data on genotype/phenotype correlations for homozygous or compound heterozygous mutations in NPHS2 and responses to CsA, CP, and methylprednisolone pulse therapies.
Although no disease-causing mutations were detected among patients with SSNS, four single heterozygous sequence variants were identified. The amino acid substitution E237Q, which occurred heterozygously in SSNS patient F3908, was observed only one more time, in SRNS patient F1086, as a single heterozygous sequence variant. No patients with homozygous or compound heterozygous mutations in NPHS2 carrying this mutation have been identified by us or others (14,15,17,18). The single heterozygous nucleotide variant could still represent a very rare polymorphism. Clear functional relevance for the recessive R138Q mutation that occurred heterozygously in SSNS patient F3147 and the R291W mutation that was identified in F1172 has been demonstrated (18,22). Although the amino acid substitutions P20L and E237Q might be polymorphisms, functional relevance for these amino acid substitutions cannot be excluded, as recently demonstrated for the common polymorphism R229Q (17,18).
In three sporadic cases (F923, F1086, and F1104) and one familial case (F376) of SRNS, only a single heterozygous sequence variant of NPHS2 was observed. Assuming a causative role of these single heterozygous sequence variants, a second mutation might have been missed or might be located in the promotor region or an intron. An interesting alternative would be the involvement of other genes in the pathogenesis of NS in these families, via the mechanism of "digenic disease" (27). The data provided in this study on mutational analyses for 285 different families with NS emphasize the relevance of mutational analysis of NPHS2 in this cohort. They present clear evidence for the importance of genotypic information to guide further treatment for these patients.
From the data provided, we draw the following conclusions. (1) Because patients with homozygous or compound heterozygous mutations in NPHS2 do not respond to standard steroid therapy for NS, we propose performing mutational analysis of NPHS2 (if consent can be obtained) for every child immediately after presentation with the first episode of NS, thus avoiding an unnecessary second trial of standard steroid therapy. (2) Because patients with SRNS and homozygous or compound heterozygous mutations in NPHS2 have reduced risks for recurrence of FSGS in a renal transplant, compared with children without mutations, living related donor transplantation might be considered more readily. (3) Additional studies with more patients will be required to delineate the genotype/phenotype correlations for homozygous or compound heterozygous mutations in NPHS2 and responses to other forms of treatment, such as CsA, tacrolimus, CP, methylprednisolone pulse therapy, or mycophenolate mofetil. (4) The significance of single heterozygous sequence variants for four of 165 families with SRNS and 4 of 120 families with SSNS must be determined in functional studies.
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-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24: 251–256, 2000[CrossRef][Medline]
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J. Am. Soc. Nephrol. 2004 15: A24-A26.
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