NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review

Genet Med. 2006 Feb;8(2):63-75. doi: 10.1097/01.gim.0000200947.09626.1c.


Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Amino Acid Substitution*
  • Case-Control Studies
  • DNA Mutational Analysis
  • Ethnic Groups
  • Gene Frequency
  • Genotype
  • Glomerulosclerosis, Focal Segmental / ethnology
  • Glomerulosclerosis, Focal Segmental / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics*
  • Nephrotic Syndrome / ethnology
  • Nephrotic Syndrome / genetics*
  • Phenotype
  • Podocytes
  • Polymorphism, Genetic


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein