Journal Article

Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis

Marije Löwik, Elena Levtchenko, Dineke Westra, Patricia Groenen, Eric Steenbergen, Jan Weening, Marc Lilien, Leo Monnens and Lambert van den Heuvel

in Nephrology Dialysis Transplantation

Published on behalf of European Renal Association - European Dialysis and Transplant Assoc

Volume 23, issue 10, pages 3146-3151
Published in print October 2008 | ISSN: 0931-0509
Published online April 2008 | e-ISSN: 1460-2385 | DOI:
Bigenic heterozygosity and the development of steroid-resistant focal segmental glomerulosclerosis

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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.

Keywords: bigenic; CD2AP; focal segmental glomerulosclerosis en podocin

Journal Article.  3804 words.  Illustrated.

Subjects: Nephrology

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