title: Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis.
abstract: BACKGROUND
  Focal segmental glomerulosclerosis (FSGS) is a major cause of steroid-resistant nephrotic syndrome in childhood with a central role for the podocytes in the pathogenesis. Mutated proteins expressed in podocytes cause proteinuria. The role of combined gene defects in the development of FSGS is less clear.
  
  
  METHODS
  We analysed seven podocyte genes known to cause proteinuria and FSGS in a group of 19 non-familial childhood-onset steroid-resistant FSGS patients. These genes include NPHS1, NPHS2, ACTN4, CD2AP, WT-1, TRPC6 and PLCE1. We also screened for the mitochondrial A3243G DNA transition associated with the MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes), and occasionally FSGS.
  
  
  RESULTS
  No mutations were found in the ACTN4 and TRPC6 genes, and no mitochondrial A3243G DNA transition was found in our group of patients. Two patients showed mutations in the CD2AP gene, one combined with an NPHS2 mutation. A tri-allelic hit was found in a patient carrying compound heterozygous NPHS2 mutations and a heterozygous NPHS1 mutation. In another patient a de novo WT-1 mutation was found combined with a heterozygous NPHS1 mutation, and finally two patients showed three heterozygous PLCE1 mutations.
  
  
  CONCLUSIONS
  In our rather small group of 19 steroid-resistant FSGS patients, we found 11 mutations in podocyte genes in 6 patients. In four of them the found mutations could explain the pathology. Our data suggest that combined gene defects in podocyte genes may play a role in the development of FSGS.
authors.affiliation: Department of Paediatric Nephrology, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Löwik
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
authors.forename: Dineke
authors.initials: D
authors.lastname: Westra
authors.forename: Patricia
authors.initials: P
authors.lastname: Groenen
authors.forename: Eric
authors.initials: E
authors.lastname: Steenbergen
authors.forename: Jan
authors.initials: J
authors.lastname: Weening
authors.forename: Marc
authors.initials: M
authors.lastname: Lilien
authors.forename: Leo
authors.initials: L
authors.lastname: Monnens
authors.forename: Lambert
authors.initials: L
authors.lastname: van den Heuvel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D016162:Genes, Wilms Tumor; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy / Q000209:etiology / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D054801:Phosphoinositide Phospholipase C / Q000235:genetics; D050199:Podocytes / Q000378:metabolism; D013256:Steroids / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D013256:Steroids; C113267:nephrin; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon