Mutational analysis of the PLCE1 gene in steroid-resistant nephrotic syndrome

Olivia Boyer (1) , Geneviève Benoit (1) , Olivier Gribouval (1) , Fabien Nevo (1) , Audrey Pawtowski (2) , Ilmay Bilge (3) , Zelal Bircan (4) , Georges Deschênes (5) , Lisa M Guay-Woodford (6) , Michelle Hall (7) , Marie-Alice Macher (5) , Kenza Soulami (8) , Constantinos J Stefanidis (9) , Robert Weiss (10) , Chantal Loirat (5) , Marie-Claire Gubler (1) , Corinne Antignac (1)

1 Neuropathies héréditaires et rein en développement
2 Service de Génétique Médicale [CHU Necker]
3 Department of Pediatrics, Istanbul Faculty of Medicine
4 Department of Pediatric Nephrology, Kocaeli University Hospital
5 AP-HP, Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris
6 Department of Genetics, UAB Center for Clinical and Translational Science, Birmingham
7 Department of Pediatric Nephrology, Hôpital Universitaire des Enfants - Reine Fabiola, Brussels
8 Service de Néphrologie Dialyse Transplantation, CHU Ibn Rochd, Casablanca
9 Department of Pediatric Nephrology,
10 Department of Pediatric Nephrology, Maria Fareri Children's Hospital, Valhalla, New York

Background: Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCε1) have been recently described in patients with early-onset nephrotic syndrome (NS) and diffuse mesangial sclerosis (DMS). In addition, two cases of PLCE1 mutations associated with focal segmental glomerulosclerosis (FSGS) and later NS onset have been reported. Methods: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, we performed mutational analysis in a worldwide cohort of 139 patients (95 familial cases belonging to 68 families and 44 sporadic cases) with steroid-resistant NS presenting at a median age of 23.0 months (range 0-373). Results: We identified homozygous or compound heterozygous mutations in 33% (8/24) of DMS cases. PLCE1 mutations were found in 8% (6/78) of FSGS cases without NPHS2 mutations. Nine were novel mutations. No clear genotype-phenotype correlation was observed, with either truncating or missense mutations detected in both DMS and FSGS, and leading to a similar renal evolution. Surprisingly, 3 unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families. Conclusion: PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although we did not identify additional variants in 19 candidate genes (16 other PLC genes, BRAF, IQGAP1 and NPHS1), we speculate that other modifier genes or environmental factors may play a role in the renal phenotype variability observed in individuals bearing PLCE1 mutations. This observation needs to be considered in the genetic counselling offered to patients.

Mots clés: Molecular genetics; Screening; Renal Medicine

Domaines: Biologie cellulaire

Olivia Boyer, Geneviève Benoit, Olivier Gribouval, Fabien Nevo, Audrey Pawtowski, et al.. Mutational analysis of the PLCE1 gene in steroid-resistant nephrotic syndrome. Journal of Medical Genetics, 2010, 47 (7), pp.445. ⟨10.1136/jmg.2009.076166⟩. ⟨hal-00557392⟩