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Severe congenital neutropenia-associated JAGN1 mutations unleash a calpain-dependent cell death programme in myeloid

Avinash Khandagale1, Teresa Holmlund1, Miriam Entesarian2,3

  • 1Division of Molecular Toxicology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

British Journal of Haematology
|November 18, 2020
PubMed

Insights

Mutations in the JAGN1 gene cause Severe Congenital Neutropenia (SCN), a condition leading to recurrent infections. These JAGN1 mutations trigger a specific calcium-dependent cell death in myeloid cells, offering new insights into SCN pathogenesis.

Area of Science:

  • Genetics
  • Immunology
  • Cell Biology

Background:

  • Severe Congenital Neutropenia (SCN), also known as Kostmann disease, is an autosomal recessive disorder.
  • SCN is characterized by a severe lack of neutrophils, increasing susceptibility to life-threatening infections.

Purpose of the Study:

  • To confirm the association between JAGN1 mutations and SCN.
  • To investigate the cellular mechanisms underlying SCN caused by JAGN1 mutations.

Main Methods:

  • Whole-exome sequencing was used to identify JAGN1 mutations in patients with Kostmann-like SCN.
  • The human promyelocytic cell line HL-60 was utilized as a model system.
  • Overexpression of patient-derived JAGN1 mutants and apoptosis-inducing stimuli were employed.

Main Results:

  • Homozygous JAGN1 mutations (p.Gly14Ser and p.Glu21Asp) were identified in three patients with SCN.
  • Overexpression of mutant JAGN1 augmented cell death in response to pro-apoptotic stimuli.
  • Mutant JAGN1 expression led to calcium-dependent cell death, preventable by calpain inhibition but not caspase inhibition.

Conclusions:

  • JAGN1 mutations are confirmed to be associated with SCN.
  • SCN-associated JAGN1 mutations induce a calcium- and calpain-dependent cell death pathway in myeloid cells.

Keywords:
apoptosiscalciumcalpainnecroptosisneutropenia

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