Master's Program of Molecular Medicine, Medical Faculty of Ulm University, Ulm, Germany.
Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany.
J Clin Immunol. 2024 Sep 12;45(1):1. doi: 10.1007/s10875-024-01799-2.
Genetic hypomorphic defects in X chromosomal IKBKG coding for the NF-κB essential modulator (NEMO) lead to ectodermal dysplasia and immunodeficiency in males and the skin disorder incontinentia pigmenti (IP) in females, respectively. NF-κB essential modulator (NEMO) Δ-exon 5-autoinflammatory syndrome (NEMO-NDAS) is a systemic autoinflammatory disease caused by alternative splicing and increased proportion of NEMO-Δex5. We investigated a female carrier presenting with IP and NEMO-NDAS due to non-skewed X-inactivation.
IKBKG transcripts were quantified in peripheral blood mononuclear cells isolated from the patient, her mother, and healthy controls using RT-PCR and nanopore sequencing. Corresponding proteins were analyzed by western blotting and flow cytometry. Besides toll-like receptor (TLR) and tumor necrosis factor (TNF) signaling, the interferon signature, cytokine production and X-inactivation status were investigated.
IP and autoinflammation with recurrent fever, oral ulcers, hepatitis, and neutropenia, but no immunodeficiency was observed in a female patient. Besides moderately reduced NEMO signaling function, type I interferonopathy, and elevated IL-18 and CXCL10 were found. She and her mother both carried the heterozygous variant c.613 C > T p.(Gln205*) in exon 5 of IKBKG previously reported in NEMO-deficient patients. However, X-inactivation was skewed in the mother, but not in the patient. Alternative splicing led to increased ratios of NEMO-Dex5 over full-length protein in peripheral blood cell subsets causing autoinflammation. Clinical symptoms partially resolved under treatment with TNF inhibitors.
Non-skewed X-inactivation can lead to NEMO-NDAS in females with IP carrying hypomorphic IKBKG variants due to alternative splicing and increased proportions of NEMO-∆ex5.
X 染色体编码 NF-κB 必需调节剂（NEMO）的基因功能缺失突变分别导致男性的埃尔德海默氏外胚层发育不全和免疫缺陷，以及女性的失禁性色素失禁症（IP）。NF-κB 必需调节剂（NEMO）Δ外显子 5-自身炎症综合征（NEMO-NDAS）是一种由剪接体异常和 NEMO-Δex5 比例增加引起的全身性自身炎症性疾病。我们研究了一名女性携带者，她因非偏性 X 染色体失活而表现出 IP 和 NEMO-NDAS。
使用 RT-PCR 和纳米孔测序从患者、其母亲和健康对照者的外周血单核细胞中定量检测 IKBKG 转录本。通过 Western 印迹和流式细胞术分析相应的蛋白质。除了 Toll 样受体（TLR）和肿瘤坏死因子（TNF）信号转导外，还研究了干扰素特征、细胞因子产生和 X 染色体失活状态。
一名女性患者表现出 IP 和自身炎症，伴有反复发热、口腔溃疡、肝炎和中性粒细胞减少，但无免疫缺陷。除了中度降低的 NEMO 信号功能、I 型干扰素病和升高的 IL-18 和 CXCL10 外，还发现了这种情况。她和她的母亲都携带了先前报道的 NEMO 缺陷患者中 IKBKG 外显子 5 中的杂合变异 c.613C > T p.（Gln205*）。然而，母亲的 X 染色体失活偏斜，而患者则没有。剪接导致外周血细胞亚群中 NEMO-Dex5 与全长蛋白的比例增加，从而引起自身炎症。在 TNF 抑制剂治疗下，临床症状部分缓解。
非偏性 X 染色体失活可导致携带 IKBKG 功能缺失突变的 IP 女性发生 NEMO-NDAS，这是由于剪接体异常和 NEMO-∆ex5 比例增加所致。
