Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, Lineu Prestes Avenue, São Paulo, SP, 1730, Brazil.
Hospital Infantil Albert Sabin, Fortaleza, CE, Brazil.
J Clin Immunol. 2024 Oct 4;45(1):21. doi: 10.1007/s10875-024-01811-9.
ISG15 deficiency is a mixed syndrome of Mendelian susceptibility to mycobacterial infections (MSMD), a rare inherited condition characterized primarily by recurrent infections from low-virulence mycobacteria and monogenic type I interferonopathy.
To characterize the laboratory and molecular features of two patients from different families affected by the same ISG15 variant.
We began with clinical characterization and investigation, assessed IL-12/IFN-γ production, performed genetic characterization through WES and Sanger sequencing, conducted an in silico molecular analysis of the genetic ISG15 variant's protein impact, and utilized RNAseq for transcriptome analysis to understand pathway impacts on ISG15-deficient subjects from unrelated families.
A mutation in the ISG15 gene was identified, affecting two patients treated in different hospitals and cities in Brazil (Fortaleza and Sao Paulo), who are also members of unrelated families. Both patients showed low IFN-γ production when stimulated with BCG or BCG + IL-12. ISG15 deficiency presented with two distinct clinical phenotypes: infectious and neurological. It was identified that both patients are homozygous for the variant (c.83 T > A). Furthermore, it was observed that the mutant protein p.L28Q results in an unstable protein with increased flexibility (ΔΔG: -2.400 kcal/mol). Transcriptome analysis revealed 1321 differentially expressed genes, with significant upregulation in interferon pathways, showing higher expression in patients compared to controls.
This study describes the first reported cases in Brazil of two unrelated patients with the same ISG15 mutation c.83 T > A, exhibiting infectious features such as mycobacterial infections and systemic candidiasis, neurological findings, and skin lesions, without adverse reactions to the BCG vaccine.
Reporting ISG15 gene mutations in Brazilian patients enhances understanding of genetic susceptibilities, guiding effective diagnostics and treatment. Identifying high-risk individuals aids clinical practices, genetic counseling, and influences public health policies. We have identified the first case in Brazil of the same ISG15 variant c.83 T > A that was identified in two unrelated patients with distinct clinical phenotypes, infectious and neurological.
ISG15 缺乏症是一种孟德尔易感性分枝杆菌感染（MSMD）的混合综合征，这是一种罕见的遗传性疾病，主要表现为低毒力分枝杆菌和单基因 I 型干扰素病的反复感染。
描述来自不同家庭的两名受同一 ISG15 变异影响的患者的实验室和分子特征。
我们首先进行临床特征描述和调查，评估 IL-12/IFN-γ 的产生，通过 WES 和 Sanger 测序进行遗传特征分析，对遗传 ISG15 变异的蛋白质影响进行计算机分子分析，并利用 RNAseq 进行转录组分析，以了解来自无关家庭的 ISG15 缺陷患者的通路影响。
在巴西（福塔雷萨和圣保罗）两家不同医院治疗的两名患者中发现了 ISG15 基因的突变，他们也来自不同的家庭。两名患者在刺激 BCG 或 BCG+IL-12 时 IFN-γ 的产生均较低。ISG15 缺乏症表现出两种不同的临床表型：感染性和神经病变。发现两名患者均为该变异的纯合子（c.83T>A）。此外，观察到突变蛋白 p.L28Q 导致蛋白质不稳定，柔韧性增加（ΔΔG：-2.400 kcal/mol）。转录组分析显示 1321 个差异表达基因，干扰素途径有显著上调，与对照相比，患者的表达更高。
本研究描述了巴西首例报告的两名无关患者携带相同的 ISG15 突变 c.83T>A，表现出感染特征，如分枝杆菌感染和系统性念珠菌病、神经病变和皮肤损伤，对卡介苗疫苗无不良反应。
在巴西患者中报告 ISG15 基因突变增强了对遗传易感性的理解，指导有效的诊断和治疗。识别高危个体有助于临床实践、遗传咨询，并影响公共卫生政策。我们已经确定了巴西首例报告的相同 ISG15 变体 c.83T>A，该变体在两名具有不同临床表型的无关患者中被识别，即感染和神经病变。
