Focal and segmental glomerulosclerosis (FSGS) is now the most common histologic pattern of injury seen in adults with primary glomerular disease. Rather than a single disease entity, FSGS describes a pattern of injury seen in kidney damage secondary to a number of identifiable primary causes but also seen as an idiopathic, isolated finding. Over the past decade, human genetic studies have confirmed the heterogeneity of the underlying biological cause of this histologic pattern. Heterozygosity for mutations in ACTN4, TRPC6, and CD2AP cause rare forms of steroid resistant FSGS.[2,3,4,5] Mutations in both NPHS2 (podocin) alleles also cause steroid resistant FSGS and are a much more common cause of FSGS than mutations in other genes identified to date. Podocin mutations appear to cause 10–30% of childhood steroid resistant nephrotic syndrome. Although genetically distinct forms of FSGS may follow different patterns of inheritance, the pattern can be difficult to identify, particularly in small families.
The clinical utility of genetic testing in the evaluation of FSGS and nephrotic syndrome in adults remains unclear. He et al found disease-segregating NPHS2 mutations in only 1 of 87 FSGS subjects analyzed. McKenzie et al have suggested that homozygous or compound heterozygous mutations in NPHS2 are very rare causes of sporadic, adult onset FSGS. They also found that heterozygotes for R138Q are more common in cases with FSGS than controls without the disease and reported that a common haplotype in NPHS2 modifies disease risk in African Americans but not European Americans.
Kidney biopsies are generally performed late in the evaluation of a nephrotic child who does not respond to steroids. Early identification of unambiguous disease-causing mutations in both NPHS2 alleles could lead to avoidance of prolonged glucocorticoid therapy and perhaps the need for kidney biopsy in these patients. The clinical utility of NPHS2 mutation analysis is much less clear in adults as there exists a broader span of underlying etiologies in the differential diagnosis in this age group and the histologic lesions underlying nephrotic and subnephrotic proteinuria overlap considerably. Here, we performed mutational analysis of NPHS2 in a large group of probands with FSGS to define the contribution of NPHS2 to late-onset disease. In addition, we genotyped two relatively common non-synonymous variants (cSNPs) in several sample sets to assess the possible contribution of these variants to albuminuria in both the general adult population and among diabetics, a group at high risk for the development of proteinuric kidney disease.
BMC Nephrology © 2008 Tonna et al; licensee BioMed Central Ltd.
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Cite this: NPHS2 Variation in Focal and Segmental Glomerulosclerosis - Medscape - Sep 29, 2008.