The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy

Pediatr Nephrol. 2008 Dec;23(12):2201-7. doi: 10.1007/s00467-008-0934-7. Epub 2008 Aug 26.


Thin-basement-membrane nephropathy (TBMN) is characterized by persistent dysmorphic hematuria, and the presence of proteinuria is a risk factor for renal impairment. TBMN is often due to mutations in the COL4A3 and COL4A4 genes, and this study determined whether additional mutations in genes encoding other structures in the glomerular filtration barrier contributed to the development of proteinuria. Fifty-six unrelated individuals with TBMN including 18 (32%) with proteinuria > or = 300 mg/L and ten (18%) with proteinuria > or = 500 mg/L were studied. Deoxyribonucleic acid (DNA) was screened for NPHS2 mutations and variants (R138Q and P375L) using single-stranded conformational analysis (SSCA) and for the R229Q mutation by sequencing. DNA was also screened for ACTN4 mutations. R229Q was more common in patients with TBMN and proteinuria > or = 500 mg/L (p < 0.05), and a possible NPHS2 mutation (671G>A, R224H) was identified in one patient with proteinuria 700 mg/L. No other NPHS2 variants correlated with proteinuria, and no ACTN4 mutations were found. Individuals with TBMN and R229Q are carriers of the autosomal recessive forms of both Alport syndrome and familial focal segmental glomerulosclerosis (FSGS). The early demonstration of R229Q in individuals with TBMN may indicate those at increased risk of proteinuria and renal impairment.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actinin / genetics
  • Adolescent
  • Adult
  • Aged
  • Autoantigens / genetics
  • Child
  • Child, Preschool
  • Collagen Type IV / genetics
  • DNA / genetics
  • Female
  • Genetic Predisposition to Disease*
  • Genetic Testing
  • Glomerular Basement Membrane / pathology*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Kidney Diseases / genetics*
  • Kidney Diseases / pathology*
  • Male
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Proteinuria / genetics*
  • Young Adult


  • ACTN4 protein, human
  • Autoantigens
  • COL4A4 protein, human
  • Collagen Type IV
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein
  • type IV collagen alpha3 chain
  • Actinin
  • DNA