title: Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome.
abstract: BACKGROUND
  Mutations in the PLCE1 gene encoding phospholipase C epsilon 1 (PLCepsilon1) 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, mutational analysis was performed 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
  Homozygous or compound heterozygous mutations were identified 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, three unaffected and unrelated individuals were also found to carry the homozygous mutations identified in their respective families.
  
  
  CONCLUSIONS
  PLCE1 is a major gene of DMS and is mutated in a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF,IQGAP1 and NPHS1) were not identified, it is speculated 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.
authors.affiliation: INSERM U983, Hôpital Necker-Enfants Malades, 149 rue de Sèvres, Paris, France.
authors.forename: Olivia
authors.initials: O
authors.lastname: Boyer
authors.forename: Geneviève
authors.initials: G
authors.lastname: Benoit
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.forename: Fabien
authors.initials: F
authors.lastname: Nevo
authors.forename: Audrey
authors.initials: A
authors.lastname: Pawtowski
authors.forename: Ilmay
authors.initials: I
authors.lastname: Bilge
authors.forename: Zelal
authors.initials: Z
authors.lastname: Bircan
authors.forename: Georges
authors.initials: G
authors.lastname: Deschênes
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Guay-Woodford
authors.forename: Michelle
authors.initials: M
authors.lastname: Hall
authors.forename: Marie-Alice
authors.initials: MA
authors.lastname: Macher
authors.forename: Kenza
authors.initials: K
authors.lastname: Soulami
authors.forename: Constantinos J
authors.initials: CJ
authors.lastname: Stefanidis
authors.forename: Robert
authors.initials: R
authors.lastname: Weiss
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000235:genetics*; D010641:Phenotype; D054801:Phosphoinositide Phospholipase C / Q000235:genetics*; D018709:Statistics, Nonparametric; D013256:Steroids / Q000627:therapeutic use
chemical_list: D013256:Steroids; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon