编码 NF-κB 必需调节剂 (NEMO) 的 X 染色体 IKBKG 的遗传性低等位缺陷分别导致男性外胚层发育不良和免疫缺陷以及女性皮肤病色素失禁 (IP)。 NF-κB 必需调节因子 (NEMO) Δ-外显子 5-自身炎症综合征 (NEMO-NDAS) 是一种由选择性剪接和 NEMO-Δex5 比例增加引起的系统性自身炎症性疾病。我们调查了一名因非偏斜 X 失活而出现 IP 和 NEMO-NDAS 的女性携带者。使用 RT-PCR 和纳米孔测序对从患者、其母亲和健康对照中分离的外周血单核细胞中的 IKBKG 转录本进行了定量。通过蛋白质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) 信号传导外，还研究了干扰素特征、细胞因子产生和 X 失活状态。 IP 和自身炎症伴反复发热、口腔溃疡、肝炎和中性粒细胞减少症，但未发现免疫缺陷在一名女性患者中观察到。除了 NEMO 信号功能中度降低外，还发现 I 型干扰素病以及 IL-18 和 CXCL10 升高。她和她的母亲都在先前报道的 NEMO 缺陷患者的 IKBKG 外显子 5 中携带杂合变异 c.613 C > T p.(Gln205*)。然而，X 染色体失活在母亲中存在偏差，但在患者中则不然。选择性剪接导致外周血细胞亚群中 NEMO-Dex5 与全长蛋白的比率增加，从而引起自身炎症。临床症状在 TNF 抑制剂治疗下部分缓解。由于选择性剪接和 NEMO-Δex5 比例增加，非偏斜 X 失活可能导致携带低效 IKBKG 变异的 IP 女性出现 NEMO-NDAS。© 2024。 ）。

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.© 2024. The Author(s).