Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Division of Pediatric Immunology, Allergy, and Rheumatology, Houston, TX 77030, USA; Instituto de Ciencias e Innovación en Medicina, Universidad del Desarrollo, Clínica Alemana de Santiago, RM 7590943, Chile.
Universitätsmedizin Greifswald, Institut für Medizinische Biochemie und Molekularbiologie, 17475 Greifswald, Germany.
Am J Hum Genet. 2018 Jun 7;102(6):1126-1142. doi: 10.1016/j.ajhg.2018.04.010. Epub 2018 May 24.
The proteasome processes proteins to facilitate immune recognition and host defense. When inherently defective, it can lead to aberrant immunity resulting in a dysregulated response that can cause autoimmunity and/or autoinflammation. Biallelic or digenic loss-of-function variants in some of the proteasome subunits have been described as causing a primary immunodeficiency disease that manifests as a severe dysregulatory syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE). Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome. Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity. We also begin to delineate a complex genetic mechanism whereby de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism. To our knowledge, this mechanism has not been reported in any primary immunodeficiencies, autoinflammatory syndromes, or autoimmune diseases. Here, we define a unique hypo- and hyper-immune phenotype and report an immune dysregulation syndrome caused by frameshift mutations that escape NMD.
蛋白酶体处理蛋白质以促进免疫识别和宿主防御。当固有缺陷时，它会导致异常免疫，从而导致失调的反应，导致自身免疫和/或自身炎症。一些蛋白酶体亚基的双等位基因或双基因功能丧失变体已被描述为导致一种原发性免疫缺陷病，表现为严重的失调综合征：慢性非典型中性粒细胞皮肤病伴脂肪营养不良和体温升高（CANDLE）。蛋白酶体成熟蛋白（POMP）是蛋白酶体组装的伴侣，对于将催化亚基掺入蛋白酶体至关重要。在这里，我们描述了在两个无关个体中发现的与 POMP 相关的自身炎症和免疫失调疾病（PRAID），这些个体具有独特的早发性联合免疫缺陷、炎症性中性粒细胞皮肤病和自身免疫的组合。我们还开始描绘一种复杂的遗传机制，即 POMP 倒数第二个外显子中的从头杂合移码变体逃避无意义介导的 mRNA 衰变（NMD），并导致截短蛋白通过显性负机制扰乱蛋白酶体组装。据我们所知，这种机制尚未在任何原发性免疫缺陷、自身炎症综合征或自身免疫性疾病中报道过。在这里，我们定义了一种独特的低免疫和高免疫表型，并报告了一种由逃避 NMD 的移码突变引起的免疫失调综合征。
