The familial idiopathic nephrotic syndromes are a heterogeneous group of kidney disorders. In 2000, a novel gene termed NPHS2 was found to segregate with a hereditary form of steroid-resistant nephrotic syndrome¹. More recent evidence supports a role for NPHS2 in sporadic nephrotic syndrome^1,2, congenital nephrotic syndrome³ and focal segmental glomerulosclerosis⁴.

Athena is pleased to offer bi-directional sequencing of the coding region of the NPHS2 gene to assist in the diagnosis of these disorders. Order NPHS2 (Podocin) Sequencing Analysis (Unit Code 710). Also available is Athena’s Nephrotic Syndrome Evaluation (Unit Code 720) for more comprehensive evaluation of your nephrotic syndrome patients.

Indications for Testing

• Nephrotic syndrome that does not appear to be responding to corticosteroid therapy
• Apparently sporadic nephrotic syndrome
• Congenital nephrotic syndrome of the Finnish type
• Congenital FSGS
• Late-onset FSGS

Steroid-Resistant Nephrotic Syndrome (SRN)

The NPHS2 gene was found to encode a novel protein that was termed podocin because it is exclusively expressed in the podocytes1. The authors point out that “…NPHS2 mutations were found in 14 of 16 families with [SRN] for which haplotype analysis was compatible with linkage to the NPHS2 locus.” They go on to say:

“It is likely that NPHS2 mutations will be found in sporadic cases of steroid-resistant idiopathic nephrotic syndrome, which represent an important cause of childhood ESRD. …The detection of NPHS2 mutations is of clinical utility; it would prescribe against unnecessary immunosuppressive therapy and permit the prediction off an absence of disease recurrence after kidney transplantation. Furthermore, it is also possible that NPHS2 might have a role in the development of secondary FSGS observed in diseases such as diabetic nephropathy, HIV nephropathy or morbid obesity.” You may wish to consider ordering Athena’s NPHS2 (Podocin) Sequencing Analysis (Unit Code 710) for your SRN patients.

Sporadic Nephrotic Syndrome

Subsequently in 2002, Karle and colleagues⁵ reported five novel mutations in NPHS2 responsible for SRN. These authors state: “Because NPHS2 mutations were found in nearly 30% of these patients with ‘sporadic’ [SRN], mutational analysis should also be performed in these patients. Besides better classification of the disease entity, identification of NPHS2 mutations may save some of these patients from unnecessary steroid treatment and also permit the prediction of absence of disease recurrence after kidney transplantation.” Other groups^6,7 have also reported NPHS2 mutations in cases of sporadic SRN. Athena’s NPHS2 (Podocin) Sequencing Analysis (Unit Code 710) may aid in your diagnosis of sporadic SRN.

Congenital Nephrotic Syndrome and Focal Segmental Glomerulosclerosis

Sequencing of the NPHS2 gene may be useful in the diagnosis of congenital nephrotic syndrome of the Finnish type (CNF), which is typically associated with alterations of the NPHS1 gene⁸. Click here for more information on Athena's testing service for CNF. It may also be useful in the diagnosis of focal segmental glomerulosclerosis (FSGS).

While most CNF patients described to date have mutations in NPHS1, recently published results3 show that NPHS2 mutations can be associated with both CNF and congenital or late-onset FSGS. In this study, 12 of the 41 CNF patients examined (29.3%) had NPHS2 mutations either in combination with or in the absence of NPHS1 mutations. Of the 8 patients with NPHS2 mutations and no NPHS1 mutations, two had a severe CNF phenotype. All four patients with both NPHS1 and NPHS2 mutations had a congenital FSGS phenotype.

The authors state “These findings…emphasise the importance of screening for both NPHS1 and NPHS2 mutations in CNF, especially when no NPHS1 mutation is apparent.” They go on to say that “…a diagnosis of CNF can result from both NPHS1 and NPHS2 mutations, and that a molecular diagnosis of congenital nephrotic syndrome should incorporate mutational analysis of both genes.”

In a separate study4, NPHS2 mutations were associated with a late-onset FSGS, and a previously reported polymorphism (R229Q) that is common in the general population was shown to be associated with FSGS when found with other NPHS2 mutations. In this important paper, NPHS2 mutations were found in 9 of 30 (30%) families with recessive FSGS.

Athena is pleased to now offer Nephrotic Syndrome Evaluation (Unit Code 720) for sequencing of the coding regions of both the NPHS1 and NPHS2 genes as an aid in the diagnosis of CNF and FSGS.

REFERENCES

1. Boute, N., et al., (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nature Genet. 24:349-354.
2. Fuchshuber, A., et al., (2001) Clinical and genetic evaluation of familial steroid-responsive nephrotic syndrome in childhood. J. Am. Soc. Nephrol. 12:374-378.
3. Koziell, A., et al., (2002) Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum. Molec. Genet. 11(4):379-388.
4. Tsukaguchi, H., et al., (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele. J. Clin. Investigation 110(11):1659-1666.
5. Karle, S., et al., (2002) Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J. Am. Soc. Nephrol. 13:388-393.
6. Fuchshuber, A., et al., (2001) Mutational analysis in patients with steroid resistant idiopathic nephrotic syndrome (srINS). Abstract FC8.6, 12th congress of the International Pediatric Nephrology Association, Seattle, WA.
7. Caridi, G., et al., (2001) Prevalence, genetics and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J. Am. Soc. Nephrol. 12:2742-2746.
8. Kestila, M., et al., (1998) Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Molec. Cell 1:575-582.