Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis.
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.
Löwik
Marije
M
Department of Paediatric Nephrology, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
Levtchenko
Elena
E
Westra
Dineke
D
Groenen
Patricia
P
Steenbergen
Eric
E
Weening
Jan
J
Lilien
Marc
M
Monnens
Leo
L
van den Heuvel
Lambert
L
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
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