1 - Unidade de Imunodeficiências Primárias, Área da Mulher, Criança e Adolescente, Hospital Dona Estefânia, Centro Hospitalar Universitário de Lisboa Central,
2 - NIH/NIAID, Laboratory of Clinical Immunology and Microbiology, Bethesda, USA.
- 18th Biennial Meeting of The European Society for Immunodeficiencies (E-Poster)
Resumo:
Background: Mammalian IRG1 protein catalyzes the decarboxylation of cis-aconitate to itaconate. Itaconate has antimicrobial activity against a variety of human pathogens; functional studies in murine macrophages have implicated itaconate as a mediator of anti-inflammatory and anti-oxidant processes. We present the case of a 15 month old girl presenting with severe and recurrent upper and lower extremity pyomyositis/abscesses caused by multiple bacteria (mostly gram negatives and anaerobes), requiring prolonged hospitalization for IV antibiotics and fasciectomies due to compartment syndrome. Recently, whole exome sequencing (WES) revealed a rare, heterozygous variant of uncertain significance (VUS) in IRG1.
We aimed to investigate the potential contribution of this IRG1 variant to the patient’s clinical phenotype and use this information to inform her clinical management.
Methods: We performed WES on DNA from the patient described above and investigated one VUS in IRG1.
Results: The heterozygous missense change identified (p.A214V; rs750627006) is rare (allele frequency: 0.00001971, no homozygotes; www.gnomad.broadinstitute.org, May, 2018). IRG1 is one of the most highly upregulated transcripts in classically activated (M1) macrophages. This residue is highly conserved across vertebrates, invertebrates and bacteria, indicating a potentially important role for this residue in the structure and/or function of IRG1. However, the significance of this residue remains unclear because the crystal structure of mammalian IRG1 has not been published.
Conclusions: IRG1 p.A214V could contribute to the patient’s presentation, however functional studies are required to determine the whether this variant alters the enzymatic activity of IRG1.
Palavras Chave: Immunoresponsive gene 1 (IRG1) Itaconate abcesses