Severe congenital neutropenia (SCN) of autosomal recessive inheritance, also known as Kostmann disease, is characterised by a lack of neutrophils and a propensity for life-threatening infections. Using whole-exome sequencing, we identified homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) in three patients with Kostmann-like SCN, thus confirming the recent attribution of JAGN1 mutations to SCN. Using the human promyelocytic cell line HL-60 as a model, we found that overexpression of patient-derived JAGN1 mutants, but not silencing of JAGN1, augmented cell death in response to the pro-apoptotic stimuli, etoposide, staurosporine, and thapsigargin. Furthermore, cells expressing mutant JAGN1 were remarkably susceptible to agonists that normally trigger degranulation and succumbed to a calcium-dependent cell death programme. This mode of cell death was completely prevented by pharmacological inhibition of calpain but unaffected by caspase inhibition. In conclusion, our results confirmed the association between JAGN1 mutations and SCN and showed that SCN-associated JAGN1 mutations unleash a calcium- and calpain-dependent cell death in myeloid cells.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839451 | PMC |
| http://dx.doi.org/10.1111/bjh.17137 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
JAGN1 (Jagunal-homolog1) is a ER-resident transmembrane protein which is part of the early secretory pathway and granulocyte colony-stimulating factor receptor mediated signaling. Autosomal recessively inherited variants in the JAGN1 gene lead to congenital neutropenia, early-onset bacterial infections, aphthosis and skin abscesses due to aberrant differentiation and maturation of neutrophils. In addition, bone metabolism disorders and a syndromic phenotype, including facial features, short stature and neurodevelopmental delay, have been reported in affected patients.
View Article and Find Full Text PDFCase report: Granulocyte-macrophage colony-stimulating factor sargramostim did not rescue the neutrophil phenotype in two patients with JAGN1-mutant severe congenital neutropenia.
Front Immunol
September 2024
Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Article Synopsis
- Patients with JAGN1 mutations experience severe congenital neutropenia, leading to high rates of bacterial infections and poor response to G-CSF therapy.
- Two unrelated patients, one pregnant and one an infant, received GM-CSF after G-CSF failure, but neither showed an increase in neutrophil counts and treatment was eventually stopped due to further declines and infections.
- Despite the promising results in a mouse model, GM-CSF therapy did not benefit the patients, highlighting the need for early evaluation for hematopoietic stem cell transplantation in these cases.
A JAGN1-associated severe congenital neutropenia zebrafish model revealed an altered G-CSFR signaling and UPR activation.
Blood Adv
August 2024
Department of Oncology, Hematology, Clinical Immunology, and Rheumatology, University Hospital Tuebingen, Tuebingen, Germany.
A variety of autosomal recessive mutations in the JAGN1 gene cause severe congenital neutropenia (CN). However, the underlying pathomechanism remains poorly understood, mainly because of the limited availability of primary hematopoietic stem cells from JAGN1-CN patients and the absence of animal models. In this study, we aimed to address these limitations by establishing a zebrafish model of JAGN1-CN.
View Article and Find Full Text PDFGenetic backgrounds and clinical characteristics of congenital neutropenias in Israel.
Eur J Haematol
August 2024
Department of Hematology-Oncology, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.
Article Synopsis
- Congenital neutropenias in Israel show a diverse genetic landscape, with a focus on severe cases, particularly highlighting the prevalence of G6PC3 variants in consanguineous populations.
- A total of 65 patients were analyzed, revealing that the majority of severe cases were linked to ELANE and G6PC3 mutations, while some had other genetic variants or conditions like cyclic neutropenia or Shwachman-Diamond syndrome.
- The study emphasizes the importance of ongoing monitoring for patients due to a significant occurrence of myeloid transformation, indicating gaps in medical understanding as some patients remain without a clear genetic diagnosis.
Discerning clinicopathological features of congenital neutropenia syndromes: an approach to diagnostically challenging differential diagnoses.
J Clin Pathol
August 2024
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts, USA
The congenital neutropenia syndromes are rare haematological conditions defined by impaired myeloid precursor differentiation or function. Patients are prone to severe infections with high mortality rates in early life. While some patients benefit from granulocyte colony-stimulating factor treatment, they may still face an increased risk of bone marrow failure, myelodysplastic syndrome and acute leukaemia.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!