Frontiers in immunology · 2026
DNAJC17 deficiency: A novel inborn error of immunity with TNF-driven autoinflammation.
СтатьяКлинический случайНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Alroqi Fayhan, Almojali Abdullah, AlJaber Abdulrahman N, Althubaiti Nouf, Alzaaqi Shouq, Almohammadi Asayel, Albahkali Sarah, Majeed Mahmoud A, Al Tuwaijri Abeer, Basmaeil Yasser, Almutairi Abduarahman, Alrasheed Abdulrahman
Аннотация
BACKGROUND: Inborn Errors of Immunity (IEI) encompass a broad spectrum of monogenic disorders with variable clinical presentations, including recurrent infections, autoimmunity, and systemic inflammation. Loss-of-function mutations in DNAJC17 have been previously linked to retinal dystrophy and hypogammaglobulinemia; however, the complete immunological phenotype and underlying autoinflammatory mechanisms remain poorly characterized.
METHODS: We conducted a comprehensive clinical, molecular, and immunological investigation of three affected individuals from two unrelated consanguineous families. Our evaluation included whole genome sequencing with systematic exclusion of alternative genetic etiologies, quantitative analysis of DNAJC17 mRNA expression, and assessment of intracellular DNAJC17 protein levels. In addition, we performed in-depth immunophenotyping of adaptive and innate immune cell subsets, cytokine profiling, and interferon-stimulated gene expression analysis, alongside longitudinal evaluation of responses to therapeutic interventions.
RESULTS: All three patients presented with early-onset retinitis pigmentosa, recurrent fever, lymphadenitis, and hypogammaglobulinemia. Sanger sequencing confirmed a homozygous variant (c.681G>A; p.Ala227=) in DNAJC17 resulting in exon 9 skipping. Comprehensive whole genome analysis excluded pathogenic variants in other immune-related genes. Quantitative RT-PCR demonstrated reduced DNAJC17 mRNA levels and flow cytometry showed decreased intracellular protein levels, consistent with a hypomorphic loss-of-function effect. Immunological evaluation revealed distinct abnormalities in T, B, and NK-cell subsets, with altered monocyte and dendritic cell populations indicating innate and adaptive immune dysregulation. Inflammatory profiling identified increased cytokine activity, including TNF-α and IL-6, alongside mild induction of interferon-stimulated genes. Conventional immunomodulatory therapies failed to achieve sustained remission. In contrast, TNF inhibitor therapy resulted in dramatic clinical improvement with normalization of inflammatory markers, sustained for over three years without significant adverse events.
CONCLUSION: Our findings establish DNAJC17 deficiency as a novel monogenic inborn error of immunity characterized by retinopathy, combined immunodeficiency, and TNF-driven autoinflammation responsive to targeted TNF blockade. The underlying immune abnormalities underscore the essential role of DNAJC17 in maintaining immune homeostasis and mitochondrial function. This work provides mechanistic insights into disease pathogenesis and establishes a rational, precision medicine therapeutic approach for this newly defined syndrome.
METHODS: We conducted a comprehensive clinical, molecular, and immunological investigation of three affected individuals from two unrelated consanguineous families. Our evaluation included whole genome sequencing with systematic exclusion of alternative genetic etiologies, quantitative analysis of DNAJC17 mRNA expression, and assessment of intracellular DNAJC17 protein levels. In addition, we performed in-depth immunophenotyping of adaptive and innate immune cell subsets, cytokine profiling, and interferon-stimulated gene expression analysis, alongside longitudinal evaluation of responses to therapeutic interventions.
RESULTS: All three patients presented with early-onset retinitis pigmentosa, recurrent fever, lymphadenitis, and hypogammaglobulinemia. Sanger sequencing confirmed a homozygous variant (c.681G>A; p.Ala227=) in DNAJC17 resulting in exon 9 skipping. Comprehensive whole genome analysis excluded pathogenic variants in other immune-related genes. Quantitative RT-PCR demonstrated reduced DNAJC17 mRNA levels and flow cytometry showed decreased intracellular protein levels, consistent with a hypomorphic loss-of-function effect. Immunological evaluation revealed distinct abnormalities in T, B, and NK-cell subsets, with altered monocyte and dendritic cell populations indicating innate and adaptive immune dysregulation. Inflammatory profiling identified increased cytokine activity, including TNF-α and IL-6, alongside mild induction of interferon-stimulated genes. Conventional immunomodulatory therapies failed to achieve sustained remission. In contrast, TNF inhibitor therapy resulted in dramatic clinical improvement with normalization of inflammatory markers, sustained for over three years without significant adverse events.
CONCLUSION: Our findings establish DNAJC17 deficiency as a novel monogenic inborn error of immunity characterized by retinopathy, combined immunodeficiency, and TNF-driven autoinflammation responsive to targeted TNF blockade. The underlying immune abnormalities underscore the essential role of DNAJC17 in maintaining immune homeostasis and mitochondrial function. This work provides mechanistic insights into disease pathogenesis and establishes a rational, precision medicine therapeutic approach for this newly defined syndrome.