A case of JAGN1 mutation presenting with atypical diabetes and immunodeficiency

Céline De Cuyper; Willem Staels; Siel Daelemans; Jesse Vanbesien; Elise Nauwynck; Inge Gies

doi:10.1515/jpem-2025-0065

Article

A case of JAGN1 mutation presenting with atypical diabetes and immunodeficiency

Céline De Cuyper , Willem Staels , Siel Daelemans , Jesse Vanbesien , Elise Nauwynck and Inge Gies

Published/Copyright: July 21, 2025

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From the journal Journal of Pediatric Endocrinology and Metabolism Volume 38 Issue 11

Abstract

Objectives

To describe the case of a young girl with severe congenital neutropenia caused by a homozygous variant in the Jagunal homolog 1 (JAGN1) gene, who later developed atypical diabetes.

Case presentation

JAGN1 deficiency disrupts neutrophil maturation, resulting in immunodeficiency and recurrent infections. Our patient also exhibited impaired humoral immunity, requiring immunoglobulin replacement therapy, which reduced infection frequency. Several years after the identification of her JAGN1 mutation, she developed atypical insulin-dependent diabetes mellitus – a condition not previously associated with JAGN1 mutations. This novel finding suggests a potential role for JAGN1 in pancreatic β-cell function.

Conclusions

This case expands the spectrum of JAGN1-related immune dysfunction and introduces a potential link between JAGN1 deficiency and diabetes. We explore possible mechanisms underlying this association, highlighting the need for further research. Clinicians should consider JAGN1 mutations in the differential diagnosis of combined immune and metabolic disorders.

Keywords: congenital neutropenia; JAGN1 ; endoplasmic reticulum stress; diabetes mellitus; immunity

Corresponding author: Céline De Cuyper, Department of Pediatrics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, Laarbeeklaan 101, 1090 Jette, Belgium, E-mail: celine.decuyper@uzbrussel.be

Acknowledgments

We would like to thank the child’s family for providing their consent to publish this case report.

Research ethics: The study had been approved by the local Ethics Committee of UZB-VUB Brussel on Sept. 4, 2024 with number 1432024000169. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).
Informed consent: Informed consent was obtained from all individuals included in this study, or their legal guardians or wards.
Author contribution: CDC wrote the original draft. IG, WS, SD, JV and EN supervised the writing. IG and JV treated the patient. The authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Use of Large Language Models, AI and Machine Learning Tools: None declared.
Conflict of interest: The authors state no conflict of interest.
Research funding: WS holds a senior clinical investigator grant from the Research Foundation Flanders (File number: 77833).
Data availability: The authors confirm that the relevant data supporting the findings of this study are available within the article. Further inquires can be directed to the corresponding author.

References

1. Khandagale, A, Lazzaretto, B, Carlsson, G, Sundin, M, Shafeeq, S, Römling, U, et al.. JAGN1 is required for fungal killing in neutrophil extracellular traps: implications for severe congenital neutropenia. J Leukoc Biol 2018;104:1199–213. https://doi.org/10.1002/jlb.4a0118-030rr.Search in Google Scholar PubMed

2. Klein, C. Genetic defects in severe congenital neutropenia: emerging insights into life and death of human neutrophil granulocytes. Annu Rev Immunol 2011;29:399–413. https://doi.org/10.1146/annurev-immunol-030409-101259.Search in Google Scholar PubMed

3. Huang, J, Xiao, Y, Xu, A, Zhou, Z. Neutrophils in type 1 diabetes. J Diabetes Investig 2016;7:652–63. https://doi.org/10.1111/jdi.12469.Search in Google Scholar PubMed PubMed Central

4. Thomas, S, Guenther, G, Rowe, JH, Platt, CD, Shimamura, A, Levy, O, et al.. Severe congenital neutropenia due to jagunal homolog 1 (JAGN1) mutation: a case report and literature review. Front Pediatr 2023;11:1223191. https://doi.org/10.3389/fped.2023.1223191.Search in Google Scholar PubMed PubMed Central

5. McDermott, DH, Malech, HL. JAGN1 mutations in severe congenital neutropenia. Br J Haematol 2021;192:9–10. https://doi.org/10.1111/bjh.17135.Search in Google Scholar PubMed

6. Hojabri, M, Farsi, Y, Jamee, M, Abolhassani, H, Khani, HHK, Karimi, A, et al.. JAGN1 mutation with distinct clinical features; two case reports and literature review. BMC Pediatr 2023;23:206. https://doi.org/10.1186/s12887-023-04024-y.Search in Google Scholar PubMed PubMed Central

7. Baris, S, Karakoc-Aydiner, E, Ozen, A, Delil, K, Kiykim, A, Ogulur, I, et al.. JAGN1 deficient severe congenital neutropenia: two cases from the same family. J Clin Immunol 2015;35:339–43. https://doi.org/10.1007/s10875-015-0156-2.Search in Google Scholar PubMed

8. Boztug, K, Järvinen, PM, Salzer, E, Racek, T, Mönch, S, Garncarz, W, et al.. JAGN1 deficiency causes aberrant myeloid cell homeostasis and congenital neutropenia. Nat Genet 2014;46:1021–7. https://doi.org/10.1038/ng.3069.Search in Google Scholar PubMed PubMed Central

9. Hagelkruys, A, Wirnsberger, G, Stadlmann, J, Wöhner, M, Horrer, M, Vilagos, B, et al.. A crucial role for Jagunal homolog 1 in humoral immunity and antibody glycosylation in mice and humans. J Exp Med 2021;218. https://doi.org/10.1084/jem.20200559.Search in Google Scholar PubMed PubMed Central

10. Smith, TD, Cunningham-Rundles, C. Detection of anti-glutamic acid decarboxylase antibodies in immunoglobulin products. J Allergy Clin Immunol Pract 2018;6:260–1. https://doi.org/10.1016/j.jaip.2017.04.042.Search in Google Scholar PubMed PubMed Central

11. Nosak, C, Silva, PN, Sollazzo, P, Moon, KM, Odisho, T, Foster, LJ, et al.. Jagn1 is induced in response to ER stress and regulates proinsulin biosynthesis. PLoS One 2016;11:e0149177. https://doi.org/10.1371/journal.pone.0149177.Search in Google Scholar PubMed PubMed Central

12. Lee, S, Cooley, L. Jagunal is required for reorganizing the endoplasmic reticulum during Drosophila oogenesis. J Cell Biol 2007;176:941–52. https://doi.org/10.1083/jcb.200701048.Search in Google Scholar PubMed PubMed Central

13. Fonseca, SG, Burcin, M, Gromada, J, Urano, F. Endoplasmic reticulum stress in beta-cells and development of diabetes. Curr Opin Pharmacol 2009;9:763–70. https://doi.org/10.1016/j.coph.2009.07.003.Search in Google Scholar PubMed PubMed Central

14. Marré, ML, James, EA, Piganelli, JD. β cell ER stress and the implications for immunogenicity in type 1 diabetes. Front Cell Dev Biol 2015;3:67. https://doi.org/10.3389/fcell.2015.00067.Search in Google Scholar PubMed PubMed Central

15. Weiss, M, Steiner, DF, Philipson, LH. Insulin biosynthesis, secretion, structure, and structure-activity relationships. In: Feingold, KR, Anawalt, B, Blackman, MR, Boyce, A, Chrousos, G, Corpas, E, et al., editors. Endotext. South Dartmouth (MA): MDText.com, Inc.; 2000.Search in Google Scholar

Received: 2025-02-04

Accepted: 2025-06-30

Published Online: 2025-07-21

Published in Print: 2025-11-25

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Articles in the same Issue

https://doi.org/10.1515/jpem-2025-0065

Keywords for this article

congenital neutropenia; JAGN1; endoplasmic reticulum stress; diabetes mellitus; immunity