The patients, aged between 5 and 12 years, exhibited the phenotypic variability associated with TMEM173-activating mutations,2-4 with lung disease and systemic inflammation being the major features ...in patient 1 (P1) and patient 3 (P3), while in patient 2 (P2) skin involvement was most prominent (Fig 1; see Supplemental Text and Table E1 in this article's Online Repository at www.jacionline.org). Modest and incomplete downregulation of ISG was recently described in splenic B cells of mice treated with tofacitinib, a JAK1/3 inhibitor, with differential signaling effects suggesting currently poorly understood facets of IFN regulation.9 In this regard, our kinetic ex vivo experiments provide insights into the rapid dynamic changes in IFN signaling secondary to JAK1 blockade.
Background PRKDC encodes for DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a kinase that forms part of a complex (DNA-dependent protein kinase DNA-PK) crucial for DNA double-strand break ...repair and V(D)J recombination. In mice DNA-PK also interacts with the transcription factor autoimmune regulator (AIRE) to promote central T-cell tolerance. Objective We sought to understand the causes of an inflammatory disease with granuloma and autoimmunity associated with decreasing T- and B-cell counts over time that had been diagnosed in 2 unrelated patients. Methods Genetic, molecular, and functional analyses were performed to characterize an inflammatory disease evocative of a combined immunodeficiency. Results We identified PRKDC mutations in both patients. These patients exhibited a defect in DNA double-strand break repair and V(D)J recombination. Whole-blood mRNA analysis revealed a strong interferon signature. On activation, memory T cells displayed a skewed cytokine response typical of TH 2 and TH 1 but not TH 17. Moreover, mutated DNA-PKcs did not promote AIRE-dependent transcription of peripheral tissue antigens in vitro . The latter defect correlated in vivo with production of anti–calcium-sensing receptor autoantibodies, which are typically found in AIRE-deficient patients. In addition, 9 months after bone marrow transplantation, patient 1 had Hashimoto thyroiditis, suggesting that organ-specific autoimmunity might be linked to nonhematopoietic cells, such as AIRE-expressing thymic epithelial cells. Conclusion Deficiency of DNA-PKcs, a key AIRE partner, can present as an inflammatory disease with organ-specific autoimmunity, suggesting a role for DNA-PKcs in regulating autoimmune responses and maintaining AIRE-dependent tolerance in human subjects.
Abstract Background Beta-propeller protein-associated neurodegeneration is a newly described X-linked dominant condition due to heterozygous mutations in WDR45 . The condition is associated with ...characteristic changes on brain magnetic resonance imaging. Previous literature relating to this disorder has not specifically referred to intracranial calcification. Methods A female patient presented with significant developmental delay in early childhood and subsequently demonstrated neurodegeneration with progressive dystonia and dementia in her third decade. Brain magnetic resonance imaging revealed low signal in the substantia nigra and both globus pallidi on T2 -weighted imaging, with no eye-of-the-tiger sign. Computed tomography revealed bilateral dense calcification of the globus pallidus. We performed Sanger sequencing of the WDR45 gene in the patient and her parents. Results We identified a heterozygous c.488del C p.Pro163Argfs*34 variant in exon 8 of WDR45 . Neither parent carried the same mutation, indicating that the molecular change had occurred de novo. Conclusions Although the characteristic features of beta-propeller protein-associated neurodegeneration were present in our patient, the observation of basal ganglia calcification was considered atypical. Previous descriptions of basal ganglia calcification in individuals with neuronal brain iron accumulation led us to review the frequency of calcification in these disorders.
Background Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called ...STING-associated vasculopathy with onset in infancy (SAVI). Objectives We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease. Methods Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed. Results Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib. Conclusions Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling.
Abstract Background: Cystic leukoencephalopathy without megalencephaly is a disorder related in some cases to RNASET2 mutations and characterized by bilateral anterior temporal subcortical cysts and ...multifocal lobar white matter lesions with sparing of central white matter structures. This phenotype significantly overlaps with the sequelae of in utero cytomegalovirus (CMV) infection, including the presence of intracranial calcification in some cases. Aicardi-Goutières syndrome (AGS) is another inherited leukodystrophy with cerebral calcification mimicking congenital infection. Clinical, radiological and biochemical criteria for the diagnosis of AGS have been established, although the breadth of phenotype associated with mutations in the AGS-related genes is much greater than previously envisaged. Patients and Methods: We describe the clinical, biochemical and radiological findings of five patients demonstrating a phenotype reminiscent of AGS. Results: All patients was found to carry biallelic mutations of RNASET2. Conclusions: Our patients illustrate the clinical and radiological overlap that can be seen between RNASET2-related leukodystrophy and AGS in some cases. Our data highlight the need to include both disorders in the same differential diagnosis, and hint at possible shared pathomechanisms related to auto-inflammation which are worthy of further investigation.
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