Mutations in the NPHS2 gene, encoding the podocyte protein, podocin, have been shown¹ to be associated with steroid-resistant nephrotic syndrome (SRN). Mutations in the NPHS1 gene, encoding the slit diaphragm protein, nephrin, have been shown² to be associated with congenital nephrotic syndrome of the Finnish type (CNF). However, recent evidence shows that NPHS2 alterations are sometimes found in CNF patients who lack NPHS1 mutations^3,4. In addition, patients with a unique phenotype have been identified with mutations in both NPHS1 and NPHS2³.

Athena is pleased to offer bi-directional sequencing of the coding regions of both the NPHS1 and NPHS2 genes for enhanced diagnostic accuracy at a reduced price to assist in the complex diagnosis of these disorders. Order Nephrotic Syndrome Evaluation (Unit Code 720).

Indications for Testing

• Congenital nephrotic syndrome of the Finnish type (proband)
• Congenital nephrotic syndrome of the Finnish type (family testing)
• In place of elevated AFP for diagnosis of CNF
• Nephrotic syndrome that does not appear to be responding to corticosteroid therapy
• Apparently sporadic nephrotic syndrome
• Congenital FSGS
• Late-onset FSGS

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 gene.³

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 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 study⁵, 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. Click here to order.

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. 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.
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. Caridi, G. et al., (2003) Broadening the spectrum of diseases related to podocin mutations. J. Am. Soc. Nephrol. 14:1278-1286.
5. 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.