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

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

Author information

1
Allergy, Immunology and Pediatric Pulmonary Institute, "Assaf-Harofeh" Medical Center, Zrifin, Israel, affilated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Limorparker@gmail.com.
2
Department of Pediatrics B, "Assaf-Harofeh" Medical Center, Zrifin, Israel, affilated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
3
Allergy, Immunology and Pediatric Pulmonary Institute, "Assaf-Harofeh" Medical Center, Zrifin, Israel, affilated to Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
4
Dyn Labs Ltd, "Assaf-Harofeh" Medical Center, Zrifin, Israel.
5
Variantyx Inc, Tel Aviv, Israel.

Abstract

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.

PMID:
30568185
DOI:
10.1038/s41390-018-0259-6

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