NDT Advance Access originally published online on December 8, 2007
Nephrology Dialysis Transplantation 2008 23(4):1291-1297; doi:10.1093/ndt/gfm759
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Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS)
1 Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA 2 Service de nephrologie, hôpital Robert-Debré, Paris, France 3 Department of Pediatrics, Unit of Nephrology, Hacettepe University, Ankara, Turkey 4 Sindh Institute of Urology and Transplantation, Karachi, Pakistan 5 Department of Pediatric Nephrology, Kinderspital Zürich, Zürich, Switzerland 6 Department of Pediatric Nephrology and Dialysis, Schneider Children's Medical Center of Israel, Petah Tiqva, Israel 7 Department of Nephrology, Mattel Children's Hospital at UCLA, Los Angeles, California, USA 8 Inserm U-574, Hôpital Necker-Enfants-Malades, Paris, France 9 Department of Medicine, Division of Nephrology University of Michigan, Ann Arbor, USA 10 Department of Human Genetics, Friedrich-Alexander-Universität, Erlangen-Nürnberg, Germany 11 Department of Pediatrics, Duke University, Durham, NC 27710 USA
Friedhelm Hildebrandt, University of Michigan Health System, 8220C MSRB III, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0646, USA. Tel: +1 734 615-7285 (office), +1 734 615-7895, -7896 (laboratories); Fax: +1 734-615-1386, -7770; Email: fhilde{at}umich.edu
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Abstract |
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Background and objectives. Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort.
Methods. We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2.
Results. The median (range) age at onset of NS was 11 (1–72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2.
Conclusions. PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment.
Keywords: IDMS; LAMB2, mutation; PLCE1, WT1
Received for publication: 23. 7.07
Accepted in revised form: 24. 9.07
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