Shared and distinct mechanisms of UBA1 inactivation across different diseases

The EMBO Journal, Journal Year: 2024, Volume and Issue: 43(10), P. 1919 - 1946

Published: Feb. 15, 2024

Abstract Most cellular ubiquitin signaling is initiated by UBA1, which activates and transfers 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 known about the underlying molecular mechanisms. Here, dissecting VEXAS-causing mutations, we discovered that p.Met41 alter cytoplasmic isoform expression, whereas other reduce catalytic activity nuclear isoforms diverse mechanisms, including aberrant oxyester formation. Strikingly, non-p.Met41 most prominently affect transthioesterification, revealing transfer enzymes as a shared property pathogenesis amongst different syndrome genotypes. A similar charging bottleneck exists in some lung cancer-associated but not spinal muscular atrophy-causing instead, render thermolabile. Collectively, our results highlight precision conformational changes required for faithful transfer, define distinct mechanisms inactivation diseases, suggest specific E1-E2 modules control aspects tissue differentiation maintenance.

Language: Английский

---

Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes

Blood, Journal Year: 2024, Volume and Issue: 144(11), P. 1221 - 1229

Published: April 30, 2024

Language: Английский

---

VEXAS‐Defining UBA1 Somatic Variants in 245,368 Diverse Individuals in the NIH All Of Us Cohort

Arthritis & Rheumatology, Journal Year: 2024, Volume and Issue: 76(6), P. 942 - 948

Published: Jan. 16, 2024

Somatic variants in UBA1 cause VEXAS, a recently described, systemic autoinflammatory disease. Research on VEXAS has largely focused highly symptomatic patients. We sought to determine the prevalence of canonical, VEXAS-associated somatic and their disease penetrance diverse, unselected population.

Language: Английский

---

Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond

The Lancet Haematology, Journal Year: 2024, Volume and Issue: 11(2), P. e160 - e167

Published: Jan. 30, 2024

Language: Английский

---

Diagnostic capabilities, clinical features, and longitudinal UBA1 clonal dynamics of a nationwide VEXAS cohort

American Journal of Hematology, Journal Year: 2023, Volume and Issue: 99(2), P. 254 - 262

Published: Dec. 18, 2023

Abstract VEXAS is a prototypic hemato‐inflammatory disease combining rheumatologic and hematologic disorders in molecularly defined nosological entity. In this nationwide study, we aimed at screenshotting the current diagnostic capabilities clinical‐genomic features of VEXAS, tracked UBA1 longitudinal clonal dynamics upon different therapeutics, including allogeneic hematopoietic cell transplant. We leveraged collaboration between Italian Society Experimental Hematology Rheumatology disseminated national survey to collect clinical molecular patient information. Overall, 13/29 centers performed genomic testing locally, Sanger sequencing (46%), next‐generation (23%), droplet digital polymerase chain reaction (8%), or combination (23%). A total 41 male patients were identified, majority (51%) with threonine substitutions Met41 hotspot, followed by valine leucine (27% 8%). Median age diagnosis was 67 years. All displayed anemia (median hemoglobin 9.1 g/dL), macrocytosis. Bone marrow vacuoles observed most cases (89%). The common association polychondritis (49%). concomitant myelodysplastic neoplasm/syndrome (MDS) diagnosed 71% ( n = 28), chiefly exhibiting lower Revised International Prognostic Scoring System risk profiles. Karyotype normal all patients, except three MDS showing ‐Y, t(12;16)(q13;q24), +8. frequently mutated gene DNMT3A 10), TET2 3). At last follow‐up, five died two progressed acute leukemia. Longitudinal demonstrated mutational clearance following collected interdisciplinary cohort, characterized heterogeneous manifestations treatments used. cases. Patients exhibited various dynamics.

Language: Английский

---

VEXAS syndrome: A review of cutaneous findings and treatments in an emerging autoinflammatory disease

Experimental Dermatology, Journal Year: 2024, Volume and Issue: 33(3)

Published: March 1, 2024

Abstract VEXAS (vacuoles, E1 enzyme, X‐linked, autoinflammatory and somatic mutation) syndrome is a novel autoinflammatory, late‐onset, disorder first identified in 2020. It caused by mutations the UBA1 gene. The most prominent clinical features reported patients are cutaneous haematological, having characteristic skin as initial presenting findings of disease. severe treatment‐resistant condition with high morbidity mortality rates. Here, we examine all case reports series through March 2023 focusing on those manifestations. We discuss these manifestations their treatment strategies. In many cases, it might be suspected diagnosed dermatologists, highlighting vital role initiating timely multidisciplinary care.

Language: Английский

---

VEXAS syndrome

International Journal of Hematology, Journal Year: 2024, Volume and Issue: unknown

Published: May 31, 2024

Abstract VEXAS syndrome is a recently identified, adult-onset autoinflammatory disease caused by somatic mutations in UBA1 . an X-linked gene encoding E1 ubiquitin activating enzyme and its mutation hematopoietic stem progenitor cells leads to their clonal expansion myeloid-skewed differentiation. are clustered at the second methionine (p.Met41), eliminating UBA1b isoform translated from p.Met41. Loss of impairs ubiquitination activates innate immune pathways, leading systemic autoinflammation manifested as recurrent fever, chondritis, pulmonary involvement, vasculitis, or neutrophilic dermatitis. frequently associated with hematological disorders such myelodysplastic (MDS), plasma cell dyscrasia venous thromboembolism. Macrocytic anemia/macrocytosis vacuoles myeloid/erythroid precursors prominent features syndrome, presence patients symptoms prompts physicians screen for variant. Treatment challenging no consistently effective therapies have been established. Anti-inflammation including glucocorticoids anti-interleukin-6 shown limited efficacy, while azacytidine JAK inhibitors ruxolitinib were found induce favorable, mid-term responses. Hematopoietic transplantation only curative option should be considered younger, fit poor prognostic factors recalcitrant symptoms.

Language: Английский

---

VEXAS syndrome: a diagnostic puzzle

RMD Open, Journal Year: 2023, Volume and Issue: 9(3), P. e003332 - e003332

Published: Aug. 1, 2023

The VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an adult-onset systemic autoinflammatory condition that caused by acquired deficiency of the UBA1 gene in hematopoietic progenitor cells. clinical spectrum currently comprises a broad range phenotypes such as vasculitis, relapsing polychondritis and Sweet’s syndrome. In past, patients have left clinicians puzzled true nature this disease has not been captured until late 2020. This viewpoint describes relevant features reviews different approaches to establish diagnosis. Finally, future directions within field inflammatory diseases somatic mutations are being discussed.

Language: Английский

---

Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome

Lara D. Veeken, Journal Year: 2023, Volume and Issue: 63(8), P. 2056 - 2064

Published: Aug. 22, 2023

Abstract Objectives To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Methods Eighty-nine Japanese clinically suspected syndrome were recruited [81 males 8 females; median age of onset 69.3 years (interquartile range 62.1–77.6)]. Peptide nucleic acid–clamping PCR (PNA-PCR), regular targeting exon 3 clustering subsequent Sanger sequencing conducted for variant screening. Partitioning digital or targeted amplicon deep was also performed to evaluate the allele frequency (VAF). We developed our predict variant-positive -negative assessed diagnostic value using receiver operating characteristics (ROC) curve analysis. Results Forty (44.9%) reported identified, including case having VAF 1.7%, highly sensitive method. Our considering >50 years, cutaneous lesions, lung involvement, chondritis macrocytic anaemia predicted (the area under total 0.908). Conclusion Genetic screening combination PNA-PCR detected high sensitivity specificity. could variants.

Language: Английский

---

Structural basis for transthiolation intermediates in the ubiquitin pathway

Nature, Journal Year: 2024, Volume and Issue: 633(8028), P. 216 - 223

Published: Aug. 14, 2024

Abstract Transthiolation (also known as transthioesterification) reactions are used in the biosynthesis of acetyl coenzyme A, fatty acids and polyketides, for post-translational modification by ubiquitin (Ub) ubiquitin-like (Ubl) proteins 1–3 . For Ub pathway, E1 enzymes catalyse transthiolation from an E1~Ub thioester to E2~Ub thioester. is also required transfer HECT (homologous E6AP C terminus) RBR (ring-between-ring) E3 ligases form E3~Ub thioesters 4–6 How isoenergetic bonds driven forward pathway remains unclear. Here we isolate mimics transient intermediates E1–Ub(T)–E2 E2–Ub(T)–E3 complexes (where T denotes a or undergoing transthiolation) using chemical strategy with native near-native capture visualize continuum structures determined single-particle cryo-electron microscopy. These accompanying biochemical experiments illuminate conformational changes Ub, E1, E2 that coordinated facilitate directional each enzyme next.

Language: Английский

---