Faculty Bibliography
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76
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
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
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
American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel
OBJECTIVE:Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality. METHODS:Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts. RESULTS:Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management. CONCLUSION/CONCLUSIONS:This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.
PMID: 40787890
ISSN: 2326-5205
CID: 5906872
Improving Outcomes in VEXAS Syndrome: The Need for Prospective Data
PMID: 39862397
ISSN: 1462-0332
CID: 5802732
The common HAQ STING allele prevents clinical penetrance of COPA syndrome
COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% of individuals, with no known mediators of protection. Recent studies implicate STING in the pathogenesis of COPA syndrome. We show that the common HAQ STING allele mediates complete clinical protection. We sequenced 35 individuals with COPA mutations, 26 affected patients and 9 unaffected carriers, finding HAQ STING co-segregation with clinical nonpenetrance. Exome sequencing identified only the mutations comprising HAQ STING as variants shared by unaffected carriers and absent in patients. Experimentally, we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling. Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome. Our study is the first report of a common and well-tolerated allele mediating complete clinical protection from a severe genetic disorder. Our findings redefine the diagnostic criteria for COPA syndrome, expose functional differences among STING alleles with broad scientific and clinical implications, and reveal a potential universal gene therapy approach for patients.
PMCID:11867111
PMID: 40014299
ISSN: 1540-9538
CID: 5801232
