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Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Beck, David B; Ferrada, Marcela A; Sikora, Keith A; Ombrello, Amanda K; Collins, Jason C; Pei, Wuhong; Balanda, Nicholas; Ross, Daron L; Ospina Cardona, Daniela; Wu, Zhijie; Patel, Bhavisha; Manthiram, Kalpana; Groarke, Emma M; Gutierrez-Rodrigues, Fernanda; Hoffmann, Patrycja; Rosenzweig, Sofia; Nakabo, Shuichiro; Dillon, Laura W; Hourigan, Christopher S; Tsai, Wanxia L; Gupta, Sarthak; Carmona-Rivera, Carmelo; Asmar, Anthony J; Xu, Lisha; Oda, Hirotsugu; Goodspeed, Wendy; Barron, Karyl S; Nehrebecky, Michele; Jones, Anne; Laird, Ryan S; Deuitch, Natalie; Rowczenio, Dorota; Rominger, Emily; Wells, Kristina V; Lee, Chyi-Chia R; Wang, Weixin; Trick, Megan; Mullikin, James; Wigerblad, Gustaf; Brooks, Stephen; Dell'Orso, Stefania; Deng, Zuoming; Chae, Jae J; Dulau-Florea, Alina; Malicdan, May C V; Novacic, Danica; Colbert, Robert A; Kaplan, Mariana J; Gadina, Massimo; Savic, Sinisa; Lachmann, Helen J; Abu-Asab, Mones; Solomon, Benjamin D; Retterer, Kyle; Gahl, William A; Burgess, Shawn M; Aksentijevich, Ivona; Young, Neal S; Calvo, Katherine R; Werner, Achim; Kastner, Daniel L; Grayson, Peter C
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

Ferrada, Marcela A; Savic, Sinisa; Ospina Cardona, Daniela; Collins, Jason Charles; Alessi, Hugh; Gutierrez-Rodrigues, Fernanda; Uthaya Kumar, Dinesh Babu; Wilson, Lorena; Goodspeed, Wendy; Topilow, James S; Paik, Julie J; Poulter, James A; Kermani, Tanaz A; Koster, Matthew J; Warrington, Kenneth; Cargo, Catherine A; Tattersall, Rachel S; Duncan, Christopher Ja; Cantor, Anna; Hoffmann, Patrycja; Payne, Elspeth M; Bonnekoh, Hanna; Krause, Karoline; Cowen, Edward W; Calvo, Katherine R; Patel, Bhavisha A; Ombrello, Amanda K; Kastner, Daniel L; Young, Neal S; Werner, Achim; Grayson, Peter C; Beck, David B
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

Beck, David B; Werner, Achim; Kastner, Daniel L; Aksentijevich, Ivona
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.
PMID: 35523963
ISSN: 1759-4804
CID: 5216652

Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency [Case Report]

Oda, Hirotsugu; Manthiram, Kalpana; Chavan, Pallavi Pimpale; Rieser, Eva; Veli, Önay; Kaya, Öykü; Rauch, Charles; Nakabo, Shuichiro; Kuehn, Hye Sun; Swart, Mariël; Wang, Yanli; Çelik, Nisa Ilgim; Molitor, Anne; Ziaee, Vahid; Movahedi, Nasim; Shahrooei, Mohammad; Parvaneh, Nima; Alipour-Olyei, Nasrin; Carapito, Raphael; Xu, Qin; Preite, Silvia; Beck, David B; Chae, Jae Jin; Nehrebecky, Michele; Ombrello, Amanda K; Hoffmann, Patrycja; Romeo, Tina; Deuitch, Natalie T; Matthíasardóttir, Brynja; Mullikin, James; Komarow, Hirsh; Stoddard, Jennifer; Niemela, Julie; Dobbs, Kerry; Sweeney, Colin L; Anderton, Holly; Lawlor, Kate E; Yoshitomi, Hiroyuki; Yang, Dan; Boehm, Manfred; Davis, Jeremy; Mudd, Pamela; Randazzo, Davide; Tsai, Wanxia Li; Gadina, Massimo; Kaplan, Mariana J; Toguchida, Junya; Mayer, Christian T; Rosenzweig, Sergio D; Notarangelo, Luigi D; Iwai, Kazuhiro; Silke, John; Schwartzberg, Pamela L; Boisson, Bertrand; Casanova, Jean-Laurent; Bahram, Seiamak; Rao, Anand Prahalad; Peltzer, Nieves; Walczak, Henning; Lalaoui, Najoua; Aksentijevich, Ivona; Kastner, Daniel L
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL-1 and SHARPIN and is essential for proper immune responses. Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease. In mice, the loss of Sharpin leads to severe dermatitis due to excessive keratinocyte cell death. Here, we report two individuals with SHARPIN deficiency who manifest autoinflammatory symptoms but unexpectedly no dermatological problems. Fibroblasts and B cells from these individuals showed attenuated canonical NF-κB responses and a propensity for cell death mediated by TNF superfamily members. Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development. Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical function of the LUBAC as a gatekeeper for cell death-mediated immune dysregulation in humans.
PMID: 38609546
ISSN: 1529-2916
CID: 5655782

Shared and distinct mechanisms of UBA1 inactivation across different diseases

Collins, Jason C; Magaziner, Samuel J; English, Maya; Hassan, Bakar; Chen, Xiang; Balanda, Nicholas; Anderson, Meghan; Lam, Athena; Fernandez-Pol, Sebastian; Kwong, Bernice; Greenberg, Peter L; Terrier, Benjamin; Likhite, Mary E; Kosmider, Olivier; Wang, Yan; Samara, Nadine L; Walters, Kylie J; Beck, David B; Werner, Achim
Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers ubiquitin to tens of E2 enzymes. Clonally acquired UBA1 missense mutations cause an inflammatory-hematologic overlap disease called VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic) syndrome. Despite extensive clinical investigation into this lethal disease, little is known about the underlying molecular mechanisms. Here, by dissecting VEXAS-causing UBA1 mutations, we discovered that p.Met41 mutations alter cytoplasmic isoform expression, whereas other mutations reduce catalytic activity of nuclear and cytoplasmic isoforms by diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 mutations most prominently affect transthioesterification, revealing ubiquitin transfer to cytoplasmic E2 enzymes as a shared property of pathogenesis amongst different VEXAS syndrome genotypes. A similar E2 charging bottleneck exists in some lung cancer-associated UBA1 mutations, but not in spinal muscular atrophy-causing UBA1 mutations, which instead, render UBA1 thermolabile. Collectively, our results highlight the precision of conformational changes required for faithful ubiquitin transfer, define distinct and shared mechanisms of UBA1 inactivation in diverse diseases, and suggest that specific E1-E2 modules control different aspects of tissue differentiation and maintenance.
PMID: 38360993
ISSN: 1460-2075
CID: 5635462

Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome

Ospina Cardona, Daniela; Rodriguez-Pinto, Ignasi; Iosim, Sonia; Bonet, Nuria; Mensa-Vilaro, Anna; Wong, Mei-Kay; Ho, Gary; Tormo, Marc; Yagüe, Jordi; Shon, Wonwoo; Wallace, Daniel; Casals, Ferran; Beck, David B; Abuav, Rachel; Arostegui, Juan I
OBJECTIVE:The vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a complex immune disorder consequence of somatic UBA1 variants. Most reported pathogenic UBA1 variants are missense or splice site mutations directly impairing the translational start site at p. Met41, with recent studies showing that these variants are frequent causes of recurrent inflammation in older individuals. Here we aimed to characterize a novel UBA1 variant found in two patients clinically presenting with VEXAS syndrome. METHODS:Patients' data were collected from direct assessments and from their medical charts. Genomics analyses were performed by both Sanger and amplicon-based deep sequencing, mRNA studies were performed by both cDNA subcloning and mRNA sequencing. RESULTS:We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids. RNA analysis from patients' samples demonstrated aberrant mRNA splicing leading to multiple in-frame transcripts, including a transcript retaining the full sequence of intron 4 and a different transcript with the deletion of the first 15 nucleotides of exon 5. CONCLUSION/CONCLUSIONS:Here we describe the abnormal UBA1 transcription as a consequence of the novel c.346-2A>G variant identified in two patients with clinical features compatible with VEXAS syndrome. Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and support for a complete gene evaluation in those candidate patients for VEXAS syndrome.
PMID: 38552317
ISSN: 1462-0332
CID: 5645302

Neutrophilic dermatosis in a patient with an IKZF1 variant and a review of monogenic autoinflammatory disorders presenting with neutrophilic dermatoses [Case Report]

Guirguis, Justina; Iosim, Sonia; Jones, Derek; Likhite, Maryel; Chen, Fei; Kesserwan, Chimene; Gindin, Tatyana; Kahn, Philip J; Beck, David; Oza, Vikash S; Hillier, Kirsty
Monogenic diseases of immune dysregulation should be considered in the evaluation of children presenting with recurrent neutrophilic dermatoses in association with systemic signs of inflammation, autoimmune disease, hematologic abnormalities, and opportunistic or recurrent infections. We report the case of a 2-year-old boy presenting with a neutrophilic dermatosis, found to have a novel likely pathogenic germline variant of the IKAROS Family Zinc Finger 1 (IKZF1) gene; the mutation likely results in a loss of function dimerization defective protein based on reports and studies of similar variants. IKZF1 variants could potentially lead to aberrant neutrophil chemotaxis and development of neutrophilic dermatoses. Long-term surveillance is required to monitor the development of hematologic malignancy, autoimmunity, immunodeficiency, and infection in patients with pathogenic IKZF1 germline variants.
PMID: 38413050
ISSN: 1525-1470
CID: 5634772

Venous and Arterial Thrombosis in Patients with VEXAS Syndrome

Kusne, Yael; Ghorbanzadeh, Atefeh; Dulau Florea, Alina; Shalhoub, Ruba N; Alcedo Andrade, Pedro Emilio; Nghiem, Khanh; Ferrada, Marcela A; Hines, Alexander; Quinn, Kaitlin A; Panicker, Sumith R; Ombrello, Amanda K; Reichard, Kaaren K; Darden, Ivana; Goodspeed, Wendy; Durrani, Jibran; Wilson, Lorena; Olteanu, Horatiu; Lasho, Terra L; Kastner, Daniel L; Warrington, Kenneth J; Mangaonkar, Abhishek A; Go, Ronald S; Braylan, Raul C; Beck, David B; Patnaik, Mrinal M; Young, Neal S; Calvo, Katherine R; Casanegra, Ana; Grayson, Peter C; Koster, Matthew J; Wu, Colin O; Kanthi, Yogendra; Patel, Bhavisha A; Houghton, Damon E; Groarke, Emma M
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, caused by somatic mutations in UBA1, is an autoinflammatory disorder with diverse systemic manifestations. Thrombosis is a prominent clinical feature of VEXAS. The risks factors and frequency of thrombosis in VEXAS are not well described, due to the disease's new discovery and paucity of large databases. We evaluated 119 VEXAS patients for venous and arterial thrombosis and correlated their presence with clinical outcomes and survival. Thrombosis occurred in 49% of patients, mostly venous thromboembolism (VTE; 41%). Almost two thirds of VTE were unprovoked, 41% were recurrent, and 20% occurred despite anticoagulation. The cumulative incidence (CI) of VTE was 17% at 1 year from symptom onset and 40% by 5 years. Cardiac and pulmonary inflammatory manifestations were associated with time to VTE. M41L was positively associated specifically with pulmonary embolism (PE) by univariate (OR: 4.58, CI 1.28-16.21; p=0.02) and multivariate (OR: 16.94, CI 1.99-144.3; p=0.01) logistic regression. The cumulative incidence of arterial thrombosis was 6% at 1 year and 11% at 5 years. The overall survival (OS) of the entire patient cohort at median follow up time of 4.8 years was 88% and there was no difference in survival between patients with or without thrombosis (p=0.8). Patients with VEXAS syndrome are at high risk of VTE; thromboprophylaxis should administered be in high-risk settings unless strongly contraindicated.
PMID: 38306657
ISSN: 1528-0020
CID: 5626972

Clonal Hematopoiesis, Inflammation, and Hematologic Malignancy

Kanagal-Shamanna, Rashmi; Beck, David B; Calvo, Katherine R
Somatic or acquired mutations are postzygotic genetic variations that can occur within any tissue. These mutations accumulate during aging and have classically been linked to malignant processes. Tremendous advancements over the past years have led to a deeper understanding of the role of somatic mutations in benign and malignant age-related diseases. Here, we review the somatic mutations that accumulate in the blood and their connection to disease states, with a particular focus on inflammatory diseases and myelodysplastic syndrome. We include a definition of clonal hematopoiesis (CH) and an overview of the origins and implications of these mutations. In addition, we emphasize somatic disorders with overlapping inflammation and hematologic disease beyond CH, including paroxysmal nocturnal hemoglobinuria and aplastic anemia, focusing on VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Finally, we provide a practical view of the implications of somatic mutations in clinical hematology, pathology, and beyond. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see for revised estimates.
PMID: 37832948
ISSN: 1553-4014
CID: 5604362

VEXAS Syndrome"”Diagnostic Clues for the Dermatologist and Gaps in Our Current Understanding: A Narrative Review

Nicholson, Lowell T.; Cowen, Edward W.; Beck, David; Ferrada, Marcela; Madigan, Lauren M.
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome is a newly recognized, acquired autoinflammatory disorder with broad systemic implications and a poor global prognosis. Because cutaneous lesions are present in the majority of those affected, it is necessary that dermatologists are equipped to recognize this important disease. Through identification, there is a greater opportunity for disease stratification, surveillance for systemic involvement, and selection of the best available therapies. As our understanding of this disease develops, dermatologists should also play a role in addressing the knowledge gaps that exist.
ISSN: 2667-0267
CID: 5630422