JAGN1 mutations in severe congenital neutropenia.

Abstract

Severe congenital neutropenia (SCN) was first clinically described in 1956 by Swedish pediatrician Rolf Kostmann, who recognized that infants who suffered from severe bacterial infections with absolute neutrophil counts (ANC) persistently below 0.5 × 109/l represented an inherited genetic disorder.1 SCN is now known to be caused by mutations in at least 25 genes and has autosomal recessive (AR), autosomal dominant (AD) and X-linked forms.2 The most common cause is due to AD mutations in the neutrophil elastase gene, ELANE, while the original disease Kostmann described was found to be due to AR mutations in HAX1.3, 4 Many of the genes causing SCN appear to be involved in endoplasmic reticulum (ER) or mitochondrial function and their disruption is involved in increasing ER stress and enhancing neutrophil apoptosis. In this issue the paper by Khandagale et al.5 whole exome sequencing techniques were applied to 27 AR SCN patients and three were found to have homozygous mutations in jagunal homolog 1 (JAGN1) which was first described as a cause of SCN in 2014 by Boztug et al.6 Jagunal was originally described as being critical for oocyte development in Drosophila via its role in ER reorganization.7 This new study further enhances our knowledge of how JAGN1 mutations can lead to ER stress and intracellular calcium activation of calpain that leads to apoptosis of myeloid cells. The experiments reported here utilized patient neutrophils, human bone marrow and the HL-60 cell line (derived from a human acute promyelocytic leukemia) to demonstrate aberrant neutrophil granules and a predilection to higher cytosolic calcium upon stimulation and enhanced calpain-dependent apoptosis in the presence of the mutant JAGN1 which could be blocked by addition of a specific inhibitor (PD150606) or by silencing JAGN1. It is of note that knocking down JAGN1 with small interfering (si)-RNA did not affect susceptibility of HL-60 cells to cell death, suggesting a dominant pathophysiologic effect of patient mutant JAGN1 on a calpain-mediated process despite an autosomal recessive pattern of inheritance. Khandagale et al. have achieved a very important breakthrough in understanding how JAGN1 mutations promote a non-apoptotic, calpain-dependent form of cell death. The authors acknowledge that further work will be needed to fully understand this pathway. The mainstay of treatment for SCN has been filgrastim since its approval by the FDA in 1991.8 It is a recombinant human granulocyte-stimulating factor that must be injected. While improving quality of life and survival by enhancing numbers and function of neutrophils in most types of SCN, long-term use has been associated with patients being at increasing risk of clonal myeloid disorders and malignancies.9 Whether this is a direct toxicity or due to prolonged survival of the patients allowing evolution of malignant clones from the prolonged pathophysiologic stress from effects of the underlying mutation remains controversial. Other experimental treatments may be appropriate in carefully selected SCN patients such as small-molecule CXCR4 inhibitors such as plerixafor or mavorixafor for WHIM syndrome,10 empagliflozin for G6PT deficiency,11 and perhaps neutrophil elastase inhibitors such as alvelestat for ELANE mutations or JAGN1 inhibitors for mutant JAGN1. Bone marrow transplantation can cure SCN, but is limited by the availability of suitable donors, and is associated with the risk of graft-versus-host disease, infectious mortality and other complications which will be improved by utilizing more specific conditioning regimens.12 Donor availability has been made less of a concern since haploidentical transplant has become more common. Genetic correction of neutrophil gene defects has already been successfully undertaken13 and may be even more practical in the future. In AD SCN, recent evidence suggests deletion of the disease allele may be a simple and effective technique without need to specifically correct the gene defect. In the case of WHIM syndrome, evidence suggests that removal of one copy of CXCR4 enhances haematopoietic stem cell engraftment and survival without the need for conditioning.14 Similarly, editing and removal of ELANE may be curative in the future.15