Mutational analysis of the PLCE1 gene in steroid resistant nephrotic syndrome

BACKGROUND: Mutationsin the PLCE1gene 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 mutationsassociated with focal segmental glomerulosclerosis(FSGS) and later NS onset have been reported. METHOD: In order to better assess the spectrum of phenotypes associated with PLCE1 mutations, mutationalanalysis 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 mutationswere identified in 33% (8/24) of DMS cases. PLCE1 mutationswere 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 mutationsdetected 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 mutationsidentified in their respective families. CONCLUSION: PLCE1is a major geneof DMS and is mutatedin a non-negligible proportion of FSGS cases without NPHS2 mutations. Although additional variants in 19 candidate genes (16 other PLC genes, BRAF, IQGAP1and 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.