Inflammatory cutaneous lesions and pulmonary manifestations in a new patient with autosomal recessive ISG15 deficiency c
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Allergy, Asthma & Clinical Immunology
LETTER TO THE EDITOR
Open Access
Inflammatory cutaneous lesions and pulmonary manifestations in a new patient with autosomal recessive ISG15 deficiency case report Guadalupe Buda1,2 , Rita María Valdez3, German Biagioli1,2, Federico A. Olivieri1, Nicolás Affranchino4, Carolina Bouso5, Vanesa Lotersztein3, Dusan Bogunovic6,7,8, Jacinta Bustamante9,10,11,12 and Marcelo A. Martí1*
Abstract Interferon-stimulated gene 15 (ISG15) was the first ubiquitin-like modifier protein identified that acts by protein conjugation (ISGylation) and is thought to modulate IFN-induced inflammation. Here, we report a new patient from a non-consanguineous Argentinian family, who was followed for recurrent ulcerative skin lesions, cerebral calcifications and lung disease. Whole Exome Sequencing (WES) revealed two novel compound heterozygous variants (c.285del and c.299_312del, NM_005101.4 GRCh37(hg19), both classified as pathogenic according to ACMG criteria) in the ISG15 gene, resulting in a complete deficiency due to disruption of the second ubiquitin domain of the corresponding protein. The clinical phenotype of this patient is unique given the presence of recurrent pulmonary manifestations and the absence of mycobacterial infections, thus resulting in a phenotype distinct from that previously described in patients with biallelic loss-of-function (LOF) ISG15 variants. This case highlights the role of ISG15 as an immunomodulating factor whose LOF variants result in heterogeneous clinical presentations. Keywords: Whole-exome sequencing, ISG15 gene, Case report, Ulcerative skin lesions, Lung disease To the Editor Interferon-stimulated gene 15 (ISG15) was the first ubiquitin-like modifier protein identified that acts by protein conjugation (ISGylation) [1]. It is one of the most upregulated genes upon Type I interferon treatment or pathogen infections, and its secreted form stimulates the production of cytokines and proliferation of NK cells in humans [2]. ISG15 is present in the gelatinase and secretory granules (but not in the azurophilic or *Correspondence: [email protected] 1 Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires (FCEyN-UBA) e Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN) CONICET, Pabellón 2 de Ciudad Universitaria, Buenos Aires, Argentina Full list of author information is available at the end of the article
specific granules) of steady-state neutrophils, which release it upon bacterial challenge [3]. ISG15 is also secreted by many other cell types, including myeloid cells, acting as a very potent interferon gamma (IFNγ) inducing cytokine in lymphocytes (particular NK cells), and in synergy with IL-12. In humans, biallelic mutations in ISG15 were reported to result in an impaired IFN-γ mediated immunity, leading to an increase predisposition to mycobacterial infections in most cases, as also observed in patients with Mendelian Susceptibility to Mycobacterial Diseases (MSMD) [4]
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