Barreto Thaís M M, Souza Roberta S, São Pedro Raquel B, Paiva Isadora M, Silva Andréia S, Nogueira Ana L, Bellinat Ana P N, Dias Nathália L S, Nunes Sara, Britto Gabriela S G, Amaral Edson H B, Rocha Gabriela D, Silva-Carvalho Carolina, Lyra Ricardo, Kehdy Fernanda S G, Campos Túlio L, Moura Patrícia M M F, Tarazona-Santos Eduardo, Cunha Thiago M, Tavares Natália M, Oliveira-Sá Marcus V B, Ramos Regina C F, Carmo Rodrigo F, Vasconcelos Luydson R S, Oliveira Pablo R S
Instituto de Biologia, Universidade Federal da Bahia, Salvador.
Emergência Pediátrica, Instituto Couto Maia, Salvador.
J Infect Dis. 2024 Dec 16;230(6):1400-1409. doi: 10.1093/infdis/jiae480.
Multisystem inflammatory syndrome in children (MIS-C) is a rare, potentially fatal complication of SARS-CoV-2 infection. Genetic defects in inflammation-related pathways have been linked to MIS-C, but additional research is needed, especially in diverse ethnic groups. The present study aimed to identify genetic variants underlying MIS-C in Brazilian patients. Whole exome sequencing was performed, focusing on genes involved in the host immune response to SARS-CoV-2. Functional assays assessed the impact of selected variants on nuclear factor-κB signaling. Nine rare, potentially deleterious variants were found in 8 of 21 patients, located in the IL17RC, IFNA10, or NLRP12 gene. Unlike the wild type NLRP12 protein, which inhibits nuclear factor-κB activation in HEK 293T cells, the mutant NLRP12 proteins have significantly reduced inhibitory properties. In conclusion, our results indicate that rare autosomal variants in immune-related genes may underlie MIS-C, highlighting the potential role of NLRP12 in its predisposition. These findings provide new insights for the appropriate management of MIS-C.
儿童多系统炎症综合征（MIS-C）是一种由严重急性呼吸综合征冠状病毒2（SARS-CoV-2）感染引起的罕见且可能致命的并发症。炎症相关通路的基因缺陷与MIS-C有关，但仍需进一步研究，尤其是在不同种族群体中。本研究旨在确定巴西患者中MIS-C潜在的基因变异。研究人员进行了全外显子组测序，重点关注宿主对SARS-CoV-2免疫反应相关的基因。功能试验评估了选定变异对核因子-κB信号传导的影响。在21名患者中的8名患者中发现了9种罕见的、可能有害的变异，这些变异位于白细胞介素17受体C（IL17RC）、α干扰素10（IFNA10）或核苷酸结合寡聚化结构域样受体蛋白12（NLRP12）基因中。与野生型NLRP12蛋白不同，野生型NLRP12蛋白可抑制人胚肾293T细胞（HEK 293T）中的核因子-κB激活，而突变型NLRP12蛋白的抑制特性则显著降低。总之，我们的结果表明，免疫相关基因中的罕见常染色体变异可能是MIS-C的潜在病因，突出了NLRP12在其易感性中的潜在作用。这些发现为MIS-C的合理治疗提供了新的见解。
