Faculty Bibliography
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76
Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
BACKGROUND:Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS:We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS:lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS:Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
PMID: 33108101
ISSN: 1533-4406
CID: 5006912
Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis
Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.
PMID: 35793467
ISSN: 1528-0020
CID: 5268432
Disorders of ubiquitylation: unchained inflammation
Ubiquitylation is an essential post-translational modification that regulates intracellular signalling networks by triggering proteasomal substrate degradation, changing the activity of substrates or mediating changes in proteins that interact with substrates. Hundreds of enzymes participate in reversible ubiquitylation of proteins, some acting globally and others targeting specific proteins. Ubiquitylation is essential for innate immune responses, as it facilitates rapid regulation of inflammatory pathways, thereby ensuring sufficient but not excessive responses. A growing number of inborn errors of immunity are attributed to dysregulated ubiquitylation. These genetic disorders exhibit broad clinical manifestations, ranging from susceptibility to infection to autoinflammatory and/or autoimmune features, lymphoproliferation and propensity to malignancy. Many autoinflammatory disorders result from disruption of components of the ubiquitylation machinery and lead to overactivation of innate immune cells. An understanding of the disorders of ubiquitylation in autoinflammatory diseases could enable the development of novel management strategies.
PMCID:9075716
PMID: 35523963
ISSN: 1759-4804
CID: 5216652
Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations
VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe inflammatory and hematologic disease caused by somatic mutations in UBA1. Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms. Studies have reported clinical differences between canonical and non-canonical mutations, but these findings are constrained by small sample sizes and scarcity of genetic studies. In our study, we screened 29,000 individuals for UBA1 variants, referred for a broad range of hematologic diseases, and subjected to 62-gene panel sequencing, identifying 232 patients carrying likely disease-causing mutations. We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations. Our findings confirm that patients harboring M41 mutations present at most with myelodysplastic neoplasms (MDS) and suggest that M41 mutations generally do not tolerate multiple co-mutations. In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS. Our study establishes that M41 and non-M41 mutations exhibit distinct clinical and biological phenotypes, significantly enhancing UBA1 variant interpretation.
PMID: 41068485
ISSN: 1476-5551
CID: 5952272
Investigating the neuronal role of the proteasomal ATPase subunit gene PSMC5 in neurodevelopmental proteasomopathies
Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor cell stemness, causing deficits in higher-order functions, including learning and locomotion. Pharmacological targeting of integrated stress response kinases reveals a mechanistic link between proteotoxic stress and spontaneous type I interferon activation. These findings expand our understanding of proteasome-dependent quality control in neurodevelopment and suggest potential therapeutic strategies for neurodevelopmental proteasomopathies.
PMCID:12658096
PMID: 41298377
ISSN: 2041-1723
CID: 5968482
Establishing a consensus definition of VEXAS flare for clinical research
OBJECTIVE:VEXAS syndrome is a severe systemic haemato-inflammatory disease with heterogeneous clinical presentations. Most patients experience recurrent inflammatory flares despite anti-inflammatory therapy. The lack of accepted definitions of flare in these patients is preventing development of disease activity tools that are essential for conducting clinical trials. We aimed to develop a consensus definition of a VEXAS flare for use in clinical trials. METHODS:A 9-member international expert advisory committee established a consensus definition of VEXAS flare using modified Delphi methodology. Clinical inflammatory manifestations of VEXAS syndrome were identified through a systematic literature review. Committee members developed a conceptual framework for flare definition, proposed revisions, and voted on changes until consensus (≥75% concurrence) was reached. RESULTS:Consensus defined VEXAS flare as active inflammatory manifestation(s) of VEXAS syndrome requiring escalation in glucocorticoid therapy. Three flare categories were established: A) recurrence of a prior documented VEXAS manifestation; B) development of a new VEXAS-defining inflammatory manifestation; or C) emergence of a new inflammatory manifestation not meeting criteria for A or B. The panel endorsed an independent adjudication committee to assess Category C flares in clinical trials. CONCLUSIONS:This study proposes a standardized definition of VEXAS flare, providing uniform criteria for identifying VEXAS disease activity. Future research will evaluate its performance in clinical trials.
PMID: 41289141
ISSN: 1462-0332
CID: 5968182
Characterizing VEXAS syndrome in women: Findings from an international multicenter study
BACKGROUND:VEXAS syndrome is an autoinflammatory disease caused by somatic UBA1 mutations on the X chromosome, predominantly affecting men. OBJECTIVE:To characterize VEXAS syndrome in women and to compare the features of VEXAS syndrome between sexes. METHODS:We conducted an international, multicenter study, including 12 women and 301 men with genetically confirmed VEXAS syndrome. Data were collected using a standardized case report form. Bone marrow analyses and molecular investigations were performed locally. RESULTS:Clinical features, age at onset, UBA1 mutation type, variant allele frequency, and mortality were comparable between sexes. Acquired X monosomy was found in 6/8 tested women. Additional clonal mutations were present in 3/5 tested women. Three additional UBA1-mutated women without typical inflammation are described separately. CONCLUSION/CONCLUSIONS:VEXAS syndrome affects women with clinical features similar to men, supporting the need for UBA1 testing in women with compatible presentations. X monosomy is common but not universal, suggesting alternative pathogenic mechanisms.
PMID: 40985189
ISSN: 1365-2796
CID: 5954262
Mapping the infectious burden in VEXAS syndrome: a systematic review and rationale for prevention
Infections are increasingly recognised as a major cause of morbidity and mortality in patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. We conducted a systematic review to characterise the infectious burden of VEXAS syndrome and propose preventive strategies. We included 57 studies (813 patients) showing that infections in patients with VEXAS syndrome were frequent, severe in 40-60% of cases, and fatal in 6-15% of cases. Pulmonary infections were most common, followed by cutaneous infections and bacteraemia. Opportunistic pathogens, such as Pneumocystis jirovecii, Legionella pneumophila, non-tuberculous mycobacteria, and varicella zoster virus, were frequently reported, even in patients not receiving immunosuppressive therapy, which suggests intrinsic immune dysfunction. Prophylaxis with co-trimoxazole (or other Pneumocystis prophylaxis, such as atovaquone or pentamidine) and valaciclovir should particularly be considered for patients at high risk of infection, including those receiving immunosuppressive therapy and those with lymphopenia, pMet41Val mutation, or previous severe or recurrent infections. Posaconazole might be appropriate in patients with neutropenia who are taking azacitidine. Vaccination against Streptococcus pneumoniae, varicella zoster virus, influenza, and SARS-CoV-2 is recommended. These data highlight the need to integrate infectious risk into VEXAS syndrome management and to evaluate preventive strategies in prospective studies.
PMID: 40915301
ISSN: 2665-9913
CID: 5937582
Clonal dominance: mutations in VEXAS syndrome take advantage of inflammation
PMID: 40481273
ISSN: 1759-4804
CID: 5862962
The Present and Future of Genetic Sequencing as Applied to Diagnosis and Management in Rheumatology
PMID: 40181789
ISSN: 2326-5205
CID: 5819362
