DIRECT ACTION OF THE HUMAN JAGN1 GENE ON THE IMMUNE SYSTEM AND INDIRECT ACTION ON THE NERVOUS SYSTEM

Letter to the Editor

J. Vecchiet^*

Department of Medicine and Ageing Sciences,“G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy.

*Correspondence to:
Jacopo Vecchiet,
Department of Medicine and Ageing Sciences,
“G. d’Annunzio” University of Chieti-Pescara,
66100 Chieti, Italy
e-mail: jacopo.vecchiet@unich.it

KEYWORDS: Jagunal homolog 1, JAGN1, gene, neutrophil, immune system, central nervous system

INTRODUCTION

Jagunal homolog 1 (JAGN1) is a crucial gene located in the endoplasmic reticulum (ER) that regulates the function of certain immune cells, such as neutrophils and B cells, and is also important for the proper production and glycosylation of antibodies (1). JAGN1 is active in neutrophil immunity against fungal infections, making it a novel regulator of neutrophils against difficult-to-eradicate pathogenic microbes (2). By affecting glycosylation through modification of the sugar molecule, it is crucial for maintaining humoral immunity which is carried out by IgG antibodies.

DISCUSSION

Although JAGN1 is not a nervous system-specific gene, it has indirect connections in various biological tissues, including the central nervous system (CNS), because it is ubiquitously expressed (3). In the brain, nerve cells depend on a well-functioning ER for the synthesis and proper folding of proteins. Mutations in JAGN1 (SCN6) can cause severe congenital neutropenia with neurological signs described in some patients (4) (Fig.1).

Fig. 1. Figure indicating the progressive steps from mutation of the JAGN1 gene located on the long arm of chromosome that leads to infection and neuroinflammation.

At the level of the CNS, the G6PC3 genetic defect can cause delayed psychomotor development, hypotonia, cognitive difficulties, and more rarely, epileptic seizures. This can interfere with neuronal development, synaptic transmission, and neuronal survival. Neutropenia can lead to recurrent infections (particularly of bacterial nature) and chronic inflammation, impacting neurodevelopment, especially in childhood.

SCN type 6 is a severe genetic neutropenic disorder characterized by very low neutrophil counts from birth and an increased risk of serious infections and mental retardation (5). This is considered a primary immunodeficiency caused by mutations in the G6PC3 gene. The disease is inherited in an autosomal recessive manner, and the G6PC3 gene is implicated in glucose metabolism and neutrophil survival. Neutrophil counts often fall below 500/µL due to a maturation defect in the bone marrow. In addition, neutrophils often undergo apoptosis, causing recurrent and severe infections. Neutrophil deficiency can manifest from birth, causing stomatitis, skin infections, and pneumonia. The G6PC3 genetic defect and neutrophil deficiency can cause congenital heart defects, growth retardation, mild facial abnormalities, urogenital abnormalities, and sometimes, pulmonary hypertension. A JAGN1 defect can lead to ER stress and altered glycosylation.

Diagnosis SCN type 6 is made by performing a complete blood count for neutropenia, bone marrow analysis for neutrophil maturation blockade, and genetic testing for the G6PC3 gene mutation (5).  Treatment involves administering granulocyte growth factor (G-CSF), antibiotics, and monitoring for infections (6).

CONCLUSIONS

The human JAGN1 gene, which is not expressed primarily as a neural regulatory gene, directly affects the regulation and functioning of the immune system. JAGN1 influences neutrophil function, protein transport in the ER, and the survival of innate immune cells. Mutations in this gene lead to immunodeficiency with recurrent infections. Therefore, JAGN1 affects the nervous system indirectly, but its effect on the immune system can lead to chronic inflammation, increased susceptibility to infections, and systemic stress responses.

Conflict of interest

The author declares that they have no conflict of interest.

REFERENCES

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