Figure 3.

Mechanism of severe congenital neutropenia caused by JAGN1 deficiency. (1) Stimuli for degranulation in a wild-type JAGN1 transmembrane protein produces degranulation. (2) Mutant JAGN1 produces ER stress. (3) ER stress results in increased Grp78 protein. (4) Elevated Grp78 causes N-glycosylation. (5) Altered N-glycosylation results in elevated calcium in the cytoplasm, causing activation of calpain, which leads to apoptosis. (6) Reduced MMP leads to Ca²⁺ entry to mitochondria, causing MPT. (7) MPT causes stimulation of AIF, which is cleaved by calpain. (8) AIF released in cytoplasm activates programmed cell death (apoptosis). Grp78—immunoglobulin heavy-chain binding protein of heat shock protein 70 family, a regulator of unfolded protein response, which is induced in cells with endoplasmic reticulum stress. They act as a molecular chaperone and a key regulator of Ca²⁺ homeostasis; GM-CSF improves N-glycosylation and is therefore used as a treatment for congenital neutropenia in JAGN1 mutation. MMP, mitochondrial membrane potential; AIF, apoptosis-inducing factor; JAGN1, jagunal homolog 1 membrane protein; MPT, mitochondrial permeability transition; Ca²⁺, calcium ion; ROS, reactive oxygen species.