Phospholipase C-Gamma 2 Activity in Familial Steroid-Sensitive Nephrotic Syndrome

Pediatr Res. 2019 Apr;85(5):719-723. doi: 10.1038/s41390-018-0259-6. Epub 2018 Dec 19.


Background: Familial Steroid-sensitive Nephrotic Syndrome (SSNS) is rare, complicating the identification of candidate genes. A recent population-based approach study of SSNS identified HLA-DQA1 and Phospholipase C-Gamma 2 (PLCG2) missense coding variants as candidate loci. PLCG2 is a signaling molecule regulated by phosphorylation and is critical for Ca2+ flux in cells of the immune system.

Methods: In order to detect a candidate gene for familial SSNS, we conducted an whole-exome sequencing in a pedigree consisting of two healthy parents, two non-identical twin brothers with SSNS, and a healthy young sibling. Flow cytometric assays were conducted to investigate the effects of the identified PLCG2 rare variants on B cell receptor-mediated PLCG2 tyrosine 759 phosphorylation, as well as on Ca2+ flux.

Results: Two missense rare variants in the PLCG2 gene were detected in the affected twins. An increase in tyrosine phosphorylation of PLCG2 as well as more rapid Ca2+ flux were noted in response to stimulation in the affected twins compared to their parents.

Conclusions: Rare variants in PLCG2 segregated with disease in familial SSNS. Functional studies suggest the combined rare variants result in a gain of function in PLCG2 activity. Taken together, these results support PLCG2 as a possible candidate locus for familial SSNS.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Antigens, CD19 / metabolism
  • Calcium / metabolism
  • Child, Preschool
  • DNA Mutational Analysis
  • Diseases in Twins
  • Exome
  • Family Health
  • Flow Cytometry
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Male
  • Mutation
  • Mutation, Missense*
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / metabolism*
  • Pedigree
  • Phenotype
  • Phospholipase C gamma / genetics
  • Phospholipase C gamma / metabolism*
  • Phosphorylation
  • Risk
  • Signal Transduction
  • Steroids / therapeutic use*


  • Antigens, CD19
  • CD19 molecule, human
  • Steroids
  • Phospholipase C gamma
  • Calcium