65 results on '"David B. Beck"'
Search Results
2. Spectrum of clonal hematopoiesis in VEXAS syndrome
- Author
-
Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna Fernandez, Terra L Lasho, Ruba N Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy M. Finke, Matthew J. Koster, Abhishek A. Mangaonkar, Kenneth J Warrington, Kebede Begna, Zhuoer Xie, Amanda K Ombrello, David S Viswanatha, Marcela A. Ferrada, Lorena Wilson, Ronald S. Go, Taxiarchis V. Kourelis, Kaaren K Reichard, Horatiu Olteanu, Ivana Darden, Dalton Hironaka, Lemlem Alemu, Sachiko Kajigaya, Rodrigo T. Calado, Emma M. Groarke, Sofia Rosenzweig, Daniel L Kastner, Katherine R Calvo, Colin O. Wu, Peter C. Grayson, Neal S Young, David B. Beck, Bhavisha A. Patel, and Mrinal M. Patnaik
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients is unknown. Retrospectively, we screened 80 VEXAS patients for CH in their peripheral blood (PB) and correlated findings with clinical outcomes in 77. UBA1mutwere most common at hotspot p.M41 (median variant allele frequency/VAF = 75%). Typical CH mutations co-occurred with UBA1mut in 60% of patients, mostly in DNMT3A and TET2, and were not associated with inflammatory or hematologic manifestations. In prospective single-cell proteogenomic sequencing (scDNA), UBA1mutwas the dominant clone, present mostly in branched clonal trajectories. Based on integrated bulk and scDNA analyses, clonality in VEXAS followed two major patterns: with either typical CH preceding UBA1mutselection in a clone (Pattern 1), or occurring as an UBA1mutsubclone or in independent clones (Pattern 2). VAF in PB differed markedly between DNMT3A and TET2 clones (median VAF of 25% vs 1%). DNMT3A and TET2 clones associated with hierarchies representing patterns 1 and 2, respectively. Overall survival for all patients was 60% at 10 years. Transfusion-dependent anemia, moderate thrombocytopenia, and typical CH mutations, each correlated with poor outcome. In VEXAS, UBA1mut cells are the primary cause of systemic inflammation and marrow failure, being a new molecularly defined somatic entity associated with MDS. VEXAS-associated MDS is distinct from classical MDS in its presentation and clinical course.
- Published
- 2023
3. A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm
- Author
-
Karen A. Moser, Peng Li, Rodney R. Miles, Lorena Wilson, David B. Beck, Tracy I. George, Shobi Venkatachalam, Tibor Kovacsovics, Daniela Ospina Cardona, and Srinivas K. Tantravahi
- Subjects
Male ,Pathology ,medicine.medical_specialty ,Myeloid ,Ubiquitin-Activating Enzymes ,Disease ,Myeloid Neoplasm ,Neoplasms ,hemic and lymphatic diseases ,medicine ,Humans ,Erythroid Precursor Cells ,Cytopenia ,Myeloproliferative Disorders ,business.industry ,Hematology ,medicine.disease ,medicine.anatomical_structure ,Vacuolization ,Myelodysplastic Syndromes ,Mutation ,Exceptional Case Report ,Macrocytic anemia ,Bone marrow ,business - Abstract
Key Points Somatic UBA1 mutations define VEXAS in men with late-onset systemic inflammatory disease and cytopenia.Features summarizing VEXAS include cytopenia, hypercellularity, lack of hematogones, and vacuoles in myeloid and erythroid precursors., VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is caused by somatic mutations in UBA1 and is identified by a genotype-driven method. This condition affects unrelated men with adultonset inflammatory syndromes in association with hematologic manifestations of peripheral cytopenia and bone marrow myeloid dysplasia. Although bone marrow vacuolization restricted to myeloid and erythroid precursors has been identified in patients with VEXAS, the detailed clinical and histopathological features of peripheral blood and bone marrows remain unclear. The current case report describes the characteristic hematologic findings in patients with VEXAS, including macrocytic anemia, thrombocytopenia, marked hypercellular bone marrow with granulocytic hyperplasia, megaloblastic changes in erythroid precursors, and the absence of hematogones in addition to prominent vacuoles in myeloid and erythroid precursor cells. Characterizing the clinical and hematologic features helps to raise awareness and improve diagnosis of this novel, rare, but potentially underrecognized disease. Prompt diagnosis expands the general knowledgeable and understanding of this disease, and optimal management may prevent patients from developing complications related to this refractory inflammatory syndrome and improve the overall clinical outcome.
- Published
- 2022
4. Human LUBAC deficiency leads to autoinflammation and immunodeficiency by dysregulation in TNF-mediated cell death
- Author
-
Hirotsugu Oda, Kalpana Manthiram, Pallavi Pimpale Chavan, Shuichiro Nakabo, Hye Sun Kuehn, David B. Beck, Jae Jin Chae, Michele Nehrebecky, Amanda K. Ombrello, Tina Romeo, Natalie Deuitch, Brynja Matthíasardóttir, Jim Mullikin, Jennifer Stoddard, Julie Niemela, Holly Anderton, Kate E. Lawlor, Hiroyuki Yoshitomi, Dan Yang, Manfred Boehm, Jeremy Davis, Pamela Mudd, Davide Randazzo, Wanxia Li Tsai, Massimo Gadina, Mariana J. Kaplan, Junya Toguchida, Christian Mayer, Sergio D. Rosenzweig, Kazuhiro Iwai, John Silke, Bertrand Boisson, Jean-Laurent Casanova, Anand Rao, Najoua Lalaoui, Ivona Aksentijevich, and Daniel L. Kastner
- Abstract
The linear ubiquitin assembly complex (LUBAC) consists of HOIP, HOIL1 and SHARPIN, and is essential for proper immune responses. Patients with HOIP and HOIL1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage. In mice, the loss ofSharpinleads to severe dermatitis due to excessive cell death in keratinocytes. Here we report the first patient with SHARPIN deficiency, manifesting fever, arthritis, colitis, chronic otitis media and hepatic glycogenosis but unexpectedly, not associated with dermatologic manifestations. Mechanistically, fibroblasts and B cells from patients with all three LUBAC deficiencies showed attenuated canonical NF-B response and propensity to apoptosis mediated by TNF superfamily members. Furthermore, the SHARPIN deficient patient showed substantial reduction of adenoidal germinal center B cell development. Treatment of the SHARPIN deficient patient with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation. These findings underscore the critical role of LUBAC as a gatekeeper for apoptosis-mediated immune dysregulation in humans.
- Published
- 2022
5. Clinical Heterogeneity of the VEXAS Syndrome
- Author
-
Kaaren K. Reichard, Kebede H. Begna, Tanaz A. Kermani, David B. Beck, Daniela Ospina Cardona, Taxiarchis Kourelis, Clement J. Michet, Jennifer L. Oliveira, Benedict K. Tiong, Mrinal M. Patnaik, Matthew J. Koster, Abhishek A. Mangaonkar, Kenneth J. Warrington, C. Christopher Hook, Michelle M. Burke, Matthew J. Samec, and Samih H. Nasr
- Subjects
medicine.medical_specialty ,Myeloid ,medicine.diagnostic_test ,Constitutional symptoms ,business.industry ,Inflammatory arthritis ,General Medicine ,medicine.disease ,Gastroenterology ,medicine.anatomical_structure ,Prednisone ,Erythrocyte sedimentation rate ,Internal medicine ,medicine ,Chondritis ,Macrocytic anemia ,Vasculitis ,business ,medicine.drug - Abstract
The objective of this study is to describe the clinical features and outcomes of patients with the newly defined vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Nine men with somatic mutations in the UBA1 gene were identified; the most frequent variant was p.Met41Thr (7 of 9, 78%). The median age at VEXAS diagnosis was 74 (67, 76.5) years, and patients had a median duration of symptoms for 4 years before diagnosis. Refractory constitutional symptoms (88%), ear and nose chondritis (55%), and inflammatory arthritis (55%) were common clinical features. Vasculitis was noted in 44%. All patients had significantly elevated inflammatory markers and macrocytic anemia. Thrombocytopenia was present in 66% at diagnosis of VEXAS. Eight patients had bone marrow biopsies performed. All bone marrows were hypercellular, and there was vacuolization of the erythroid (100%) or myeloid precursors (75%). Glucocorticoids attenuated symptoms at prednisone doses ≥20 mg per day, but no other immunosuppressive agent showed consistent long-term control of disease. One patient with coexisting plasma-cell myeloma received plasma-cell-directed therapy with improvement of the inflammatory response, which is a novel finding. In conclusion, VEXAS syndrome is a clinically heterogeneous, treatment-refractory inflammatory condition caused by somatic mutation of the UBA1 gene. Patients often present with overlapping rheumatologic manifestations and persistent hematologic abnormalities. As such, internists and subspecialists, including pathologists, should be aware of this condition to avert diagnostic delay, now that the etiology of this syndrome is known.
- Published
- 2021
6. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS
- Author
-
Wanxia L. Tsai, Robert A. Colbert, Marcus Y Chen, Arlene Sirajuddin, Ryan S. Laird, Peter C. Grayson, Patrycja Hoffmann, Sinisa Savic, Marcela A. Ferrada, Emma M. Groarke, Kristina V. Wells, Massimo Gadina, Bhavisha A Patel, Mariana J. Kaplan, Keith A. Sikora, Emily Rose, Lorena Wilson, Daniel L. Kastner, Gustaf Wigerblad, Zuoming Deng, Amanda K. Ombrello, Oskar Schnappauf, Emily Rominger, Kaitlin A. Quinn, Daniela Ospina Cardona, Jeff Kim, Ivona Aksentijevich, Neal S. Young, David B. Beck, Wendy Goodspeed, Clint T. Allen, Mimi T. Le, Katherine R. Calvo, Yiming Luo, and Anne Jones
- Subjects
030203 arthritis & rheumatology ,0301 basic medicine ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,Costochondritis ,Mortality rate ,Immunology ,medicine.disease ,Gastroenterology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,Chondritis ,Macrocytic anemia ,business ,Exome ,Mean corpuscular volume ,Relapsing polychondritis ,Multiple myeloma - Abstract
Objective Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Methods Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Results Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count
- Published
- 2021
7. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1
- Author
-
Fernanda Gutierrez-Rodrigues, Daniel L. Kastner, David B. Beck, Patrycja Hoffmann, Marcela A. Ferrada, Bhavisha A Patel, Nisha Patel, Megan Trick, Neal S. Young, Peter C. Grayson, Zhijie Wu, Ifeyinwa Emmanuela Obiorah, Daniela Ospina Cardona, Alina Dulau-Florea, Lorena Wilson, Emma M. Groarke, Weixin Wang, Katherine R. Calvo, Jennifer Lotter, and Amanda K. Ombrello
- Subjects
Male ,medicine.medical_specialty ,Myeloid ,Neutropenia ,Monoclonal Gammopathy of Undetermined Significance ,Gastroenterology ,Bone Marrow ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Multiple myeloma ,Myeloid Neoplasia ,business.industry ,Myelodysplastic syndromes ,Hematology ,medicine.disease ,Leukemia ,medicine.anatomical_structure ,Hematologic disease ,Myelodysplastic Syndromes ,Mutation ,Macrocytic anemia ,Multiple Myeloma ,business ,Monoclonal gammopathy of undetermined significance - Abstract
Somatic mutations in UBA1 involving hematopoietic stem and myeloid cells have been reported in patients with the newly defined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. Here, we report clinical hematologic manifestations and unique bone marrow (BM) features in 16 patients with VEXAS. All patients were male and had a history of severe autoinflammatory and rheumatologic manifestations and a somatic UBA1 mutation (p.Met41). Ten patients had hematologic disorders: myelodysplastic syndrome (MDS; 6 of 16), multiple myeloma (2 of 16), monoclonal gammopathy of undetermined significance (2 of 16), and monoclonal B-cell lymphocytosis (2 of 16), and a few of those patients had 2 co-existing clonal processes. Although macrocytic anemia (100%) and lymphopenia (80%) were prevalent in all patients with VEXAS, thrombocytopenia and neutropenia were more common in patients with progression to MDS. All BMs in VEXAS patients had prominent cytoplasmic vacuoles in myeloid and erythroid precursors. In addition, most BMs were hypercellular with myeloid hyperplasia, erythroid hypoplasia, and varying degrees of dysplasia. All patients diagnosed with MDS were lower risk (low blast count, very good to intermediate cytogenetics) according to standard prognostic scoring with no known progression to leukemia. In addition, 10 of 16 patients had thrombotic events, including venous thromboembolism and arterial stroke. Although VEXAS presents symptomatically as a rheumatologic disease, morbidity and mortality are associated with progression to hematologic disease. Given the increased risk of developing MDS and multiple myeloma, surveillance for disease progression is important.
- Published
- 2021
8. A tissue-specific ubiquitin switch coordinates brain, craniofacial, and skin development
- Author
-
Anthony J. Asmar, Rita M. Yazejian, Youmei Wu, Jason C. Collins, Jenny Hsin, Jean Cho, Andrew D. Doyle, Samhitha Cinthala, Marleen Simon, Richard H. van Jaarsveld, David B. Beck, Laura Kerosuo, and Achim Werner
- Abstract
The molecular mechanisms that coordinate patterning of the embryonic ectoderm into spatially distinct lineages to form the nervous system, epidermis, and craniofacial structures are unclear. Here, biochemical disease-variant profiling reveals a posttranslational pathway that drives early ectodermal differentiation in the vertebrate head. The anteriorly expressed ubiquitin ligase CRL3-KLHL4 restricts signaling of the ubiquitous cytoskeletal regulator CDC42. The major substrate of CRL3-KLHL4 is the canonical CDC42 effector kinase PAK1 that monoubiquitylation switches into a CDC42 inhibitor. Loss of CRL3-KLHL4 or a disease-associated KLHL4 variant reduce PAK1 ubiquitylation causing overactivation of CDC42 signaling and defective ectodermal patterning and neurulation. Thus, tissue-specific, ubiquitin-dependent restriction of CDC42 signaling is essential for face, brain, and skin formation, demonstrating how cell-fate and morphometric changes are coordinated for faithful organ development.
- Published
- 2022
9. Genomic ascertainment for UBA1 variants and VEXAS syndrome: a population-based study
- Author
-
David B. Beck, Dale L. Bodian, Vandan Shah, Uyenlinh L. Mirshahi, Jung Kim, Yi Ding, Natasha T. Strande, Anna Cantor, Jeremy S. Haley, Adam Cook, Wesley Hill, Peter C. Grayson, Marcela A. Ferrada, Daniel L. Kastner, David J. Carey, and Douglas R. Stewart
- Abstract
ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes. This study used a genomic ascertainment approach to overcome these limitations and better define UBA1-related disease.ObjectiveDetermine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, Setting and ParticipantsThis cohort study evaluated UBA1 variants in exome data from 163,096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record (EHR) data up to January 1st, 2022.Main outcomes and measuresPrevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other symptoms in individuals with somatic UBA1 variation; structured and manual review of EHR; review of bone marrow biopsies; survival in carriers of somatic UBA1 variation.ResultsIn a retrospective study of 163,096 participants (mean age 52.8 years; 94% of European ancestry, 61% female), 11 individuals harbored somatic, known pathogenic UBA1 variants, with 100% having clinical manifestations consistent with VEXAS syndrome. We found a previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) in a symptomatic patient. Disease-causing UBA1 variants were found in ∼1 in 14,000 unrelated individuals, and ∼1 in 4,000 men >50 years old. A disease-causing UBA1 variant confers a ∼ 6.6 higher probability of mortality vs. age-, sex-, and BMI-matched non-carriers. The majority (7, 58%) of individuals did not meet criteria for rheumatologic and hematologic diagnoses previously associated with VEXAS syndrome, however all individuals had anemia (mean 7.8 g/dL, median 7.5g/dL), mostly macrocytic (91%) with concomitant thrombocytopenia (91%). Finally, we identified a pathogenic variant in one male prior to onset of VEXAS-related signs or symptoms and two females had disease with heterozygous variants.Conclusions and relevanceThis cohort study showed that the prevalence, penetrance, and expressivity of pathogenic UBA1 variants were higher than expected. More expansive UBA1 testing will lead to molecular diagnoses and improved treatment for patients.
- Published
- 2022
10. <scp>VEXAS</scp> syndrome with systemic lupus erythematosus: expanding the spectrum of associated conditions
- Author
-
Aman Sharma, David B. Beck, Prateek Deo, and Gsrsnk Naidu
- Subjects
Pathology ,medicine.medical_specialty ,Myeloid ,Polyarteritis nodosa ,Somatic cell ,business.industry ,Immunology ,Inflammation ,medicine.disease ,Giant cell arteritis ,medicine.anatomical_structure ,Rheumatology ,hemic and lymphatic diseases ,medicine ,Immunology and Allergy ,Bone marrow ,medicine.symptom ,business ,Multiple myeloma ,Relapsing polychondritis - Abstract
Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome was recently identified by genotype-driven approach. This syndrome is characterised by the presence of somatic mutations affecting methionine-41 (p.Met41) in UBA1 gene. All the identified patients were adult males who had recurrent fevers, cytopenias, dysplastic bone marrow with vacuoles in myeloid and erythroid precursors, neutrophilic skin and lung tissue inflammation and often had treatment refractory and fatal disease course. The various phenotypes reported with VEXAS syndrome include relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, Sweet's syndrome, myelodysplastic syndrome and multiple myeloma.
- Published
- 2021
11. Clonal Hematopoiesis in Vexas Syndrome
- Author
-
Bhavisha A. Patel, Fernanda Gutierrez-Rodrigues, Yael Kusne, Jenna A. Fernandez, Terra Lasho, Ruba Shalhoub, Xiaoyang Ma, Hugh Alessi, Christy Finke, Matthew Koster, Abhishek A. Mangaonkar, Kenneth Warrington, Kebede H. Begna, Zhuoer Xie, Amanda Ombrello, David S. Viswanatha, Marcela Ferrada, Lorena Wilson, Ronald Go, Taxiarchis Kourelis, Kaaren K. Reichard, Horatiu Olteanu, Emma M. Groarke, Ivana Darden, Dalton Hironaka, Sofia Rosenzweig, Daniel L. Kastner, Katherine R. Calvo, Colin O. Wu, Peter C. Grayson, David B. Beck, Mrinal M.M. Patnaik, and Neal S. Young
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
12. Thrombotic Manifestations in Patients with Vexas Syndrome
- Author
-
Pedro E. Alcedo Andrade, Ruba Shalhoub, Alina Dulau-Florea, Khanh Nghiem, Marcela Ferrada, Lorena Wilson, Ivana Darden, Wendy Goodspeed, Katherine R. Calvo, David B. Beck, Daniel L. Kastner, Peter C. Grayson, Neal S. Young, Colin O. Wu, Yogendra Kanthi, Bhavisha A. Patel, and Emma M. Groarke
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
13. Novel Disease-Causing Mutations in UBA1 Reveal Disease Mechanisms in Bone Marrow Failure and Inflammation
- Author
-
Jason C Collins, Nicholas Balanda, Samuel J Magaziner, Maya English, Daniela Ospina Cardona, Mrinal M. Patnaik, Benjamin Terrier, Olivier Kosmider, Achim Werner, and David B. Beck
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
14. DNMT3A/TET2 Mutant Clonal Hematopoiesis in Vexas Syndrome Results in DNA Hypomethylation and Transcriptional Activation of WT1 and MPL Oncogenic Pathways
- Author
-
Jenna A. Fernandez, Bhavisha A. Patel, Fernanda Gutierrez-Rodrigues, Yael Kusne, Terra Lasho, Christy Finke, Matthew Koster, Abhishek A. Mangaonkar, Naseema Gangat, Kenneth Warrington, Kaaren K. Reichard, Horatiu Olteanu, Peter C. Grayson, Neal S. Young, David B. Beck, and Mrinal M. Patnaik
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
15. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis
- Author
-
Marcela A. Ferrada, Sinisa Savic, Daniela Ospina Cardona, Jason C. Collins, Hugh Alessi, Fernanda Gutierrez-Rodrigues, Dinesh Babu Uthaya Kumar, Lorena Wilson, Wendy Goodspeed, James S. Topilow, Julie J. Paik, James A. Poulter, Tanaz A. Kermani, Matthew J. Koster, Kenneth J. Warrington, Catherine Cargo, Rachel S. Tattersall, Christopher J. A. Duncan, Anna Cantor, Patrycja Hoffmann, Elspeth M. Payne, Hanna Bonnekoh, Karoline Krause, Edward W. Cowen, Katherine R. Calvo, Bhavisha A. Patel, Amanda K. Ombrello, Daniel L. Kastner, Neal S. Young, Achim Werner, Peter C. Grayson, and David B. Beck
- Subjects
Nucleotides ,Mutation ,Immunology ,Ubiquitination ,Codon, Initiator ,Humans ,Ubiquitin-Activating Enzymes ,Cell Biology ,Hematology ,Biochemistry - Abstract
Somatic mutations in UBA1 cause vacuoles, E1 ubiquitin-activating enzyme, X-linked, autoinflammatory somatic (VEXAS) 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, whereas 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 3 canonical VEXAS variants produce more UBA1b than any of the 6 other possible single-nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with 2 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 coexpression 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.
- Published
- 2022
16. Novel genetic mutation in myositis-variant of VEXAS syndrome
- Author
-
James S Topilow, Daniela Ospina Cardona, David B Beck, Marcela A Ferrada, Zsuzsanna H McMahan, and Julie J Paik
- Subjects
Rheumatology ,Mutation ,Humans ,Pharmacology (medical) ,Ubiquitin-Activating Enzymes ,Published Online Only - Published
- 2022
17. VEXAS syndrome: An inflammatory and hematologic disease
- Author
-
David B. Beck, Marcela A. Ferrada, Bhavisha A Patel, and Peter C. Grayson
- Subjects
medicine.medical_specialty ,Hematologic disease ,business.industry ,Internal medicine ,medicine ,Humans ,Syndrome ,Hematology ,business ,medicine.disease ,Hematologic Diseases ,Gastroenterology - Published
- 2021
18. Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome—clinical presentation of a newly described somatic, autoinflammatory syndrome
- Author
-
Faris Alhomida, Dorota Lebiedz-Odrobina, Tibor Kovacsovics, Tracy I. George, David B. Beck, Andrew Shaffer, and Lauren M. Madigan
- Subjects
chemistry.chemical_classification ,business.industry ,Somatic cell ,neutrophilic dermatitis ,Sweet Syndrome ,Sweet syndrome ,Dermatology ,Vacuole ,autoinflammation ,Autoinflammatory Syndrome ,myelodysplastic syndrome ,Enzyme ,chemistry ,RL1-803 ,Immunology ,MDS ,Medicine ,genetics ,Presentation (obstetrics) ,business - Published
- 2021
19. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease
- Author
-
Sarthak Gupta, Amanda K. Ombrello, Emily Rominger, Megan Trick, Karyl S. Barron, Ryan S. Laird, Sinisa Savic, Shuichiro Nakabo, Daniela Ospina Cardona, Ivona Aksentijevich, Carmelo Carmona-Rivera, Gustaf Wigerblad, Mariana J. Kaplan, Emma M. Groarke, Laura W. Dillon, Chyi-Chia Richard Lee, Kalpana Manthiram, Kristina V. Wells, Nicholas Balanda, Zhijie Wu, Helen J. Lachmann, Daniel L. Kastner, Fernanda Gutierrez-Rodrigues, Achim Werner, Michele Nehrebecky, Lisha Xu, Alina Dulau-Florea, Wanxia L. Tsai, Bhavisha A Patel, Stefania Dell'Orso, Weixin Wang, Anthony J. Asmar, Danica Novacic, Katherine R. Calvo, David B. Beck, Robert A. Colbert, Massimo Gadina, William A. Gahl, Wendy Goodspeed, Natalie Deuitch, Dorota Rowczenio, Peter C. Grayson, Daron L. Ross, Sofia Rosenzweig, Anne Jones, Christopher S. Hourigan, James C. Mullikin, Stephen R. Brooks, Jason C. Collins, Wuhong Pei, May Christine V. Malicdan, Neal S. Young, Shawn M. Burgess, Keith A. Sikora, Mones Abu-Asab, Kyle Retterer, Patrycja Hoffmann, Hirotsugu Oda, Marcela A. Ferrada, Zuoming Deng, Benjamin D. Solomon, and Jae Jin Chae
- Subjects
Genetics ,Mutation ,Somatic cell ,business.industry ,Sequence analysis ,General Medicine ,UBA1 ,030204 cardiovascular system & hematology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Genotype ,Medicine ,Missense mutation ,030212 general & internal medicine ,Age of onset ,business ,Gene - Abstract
Background Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may...
- Published
- 2020
20. Deubiquitylases in developmental ubiquitin signaling and congenital diseases
- Author
-
David B. Beck, Achim Werner, and Mohammed Abul Basar
- Subjects
Congenital diseases ,Zygote ,Deubiquitinating Enzymes ,Disease genetics ,Ubiquitin ,Cellular differentiation ,Ubiquitination ,Cellular functions ,Review Article ,Cell Biology ,Human physiology ,Biology ,Deubiquitylating enzymes ,Embryonic stem cell ,Congenital Abnormalities ,Cell biology ,biology.protein ,Animals ,Humans ,Protein Processing, Post-Translational ,Molecular Biology ,Neurological disorders ,Organism ,Signal Transduction - Abstract
Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate’s stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.
- Published
- 2020
21. The systemic autoinflammatory diseases: Coming of age with the human genome
- Author
-
David B. Beck, Elaine F. Remmers, Yong Hwan Park, Daniel L. Kastner, Jae Jin Chae, Kalpana Manthiram, and Deborah L. Stone
- Subjects
Inflammation ,Genetics ,Genome, Human ,Mosaicism ,Immunology ,High-Throughput Nucleotide Sequencing ,Biology ,DNA sequencing ,Autoimmune Diseases ,Somatic mosaicism ,Genetic linkage ,Humans ,Immunology and Allergy ,Human genome ,Genome-Wide Association Study - Published
- 2020
22. VEXAS Syndrome and Disease Taxonomy in Rheumatology
- Author
-
Peter C. Grayson, David B. Beck, Marcela A. Ferrada, Peter A. Nigrovic, and Daniel L. Kastner
- Subjects
Rheumatology ,Immunology ,Immunology and Allergy - Published
- 2022
23. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study
- Author
-
Maël Heiblig, Marcela A. Ferrada, Matthew T. Koster, Thomas Barba, Mathieu Gerfaud-Valentin, Arsène Mékinian, Henrique Coelho, Gaelle Fossard, Fiorenza Barraco, Lionel Galicier, Boris Bienvenu, Pierre Hirsch, Guillaume Vial, Anne Blandine Boutin, Joris Galland, Guillaume Le Guenno, Adrien Bigot, Kenneth J. Warrington, Tanaz A. Kermani, Peter C. Grayson, Bhavisha A. Patel, David B. Beck, Yvan Jamilloux, Pierre Fenaux, and Pierre Sujobert
- Subjects
Pyrimidines ,Myelodysplastic Syndromes ,Immunology ,Nitriles ,Janus Kinase Inhibitors ,Pyrazoles ,Skin Diseases, Genetic ,Cell Biology ,Hematology ,Biochemistry ,Retrospective Studies - Abstract
VEXAS syndrome (vacuoles in myeloid progenitors, E1 ubiquitin activating enzyme, X-linked, autoinflammatory manifestations and somatic) is an autoinflammatory condition caused by somatically acquired UBA1 mutations. Heiblig et al report on an international retrospective analysis of 30 patients with VEXAS syndrome treated with different Janus kinase (JAK) inhibitors, finding encouraging evidence supporting the use of the JAK1/2 inhibitor ruxolitinib with clinical remissions and reductions in steroid use seen in the majority of patients.
- Published
- 2022
24. Disorders of ubiquitylation: unchained inflammation
- Author
-
David B, Beck, Achim, Werner, Daniel L, Kastner, and Ivona, Aksentijevich
- Subjects
Inflammation ,Ubiquitin ,Ubiquitination ,Humans ,Protein Processing, Post-Translational ,Immunity, Innate - Abstract
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.
- Published
- 2022
25. Deficiency of Adenosine Deaminase 2 (DADA2): Hidden Variants, Reduced Penetrance, and Unusual Inheritance
- Author
-
Oskar Schnappauf, Qing Zhou, Natalia Sampaio Moura, Amanda K. Ombrello, Drew G. Michael, Natalie Deuitch, Karyl Barron, Deborah L. Stone, Patrycja Hoffmann, Michael Hershfield, Carolyn Applegate, Hans T. Bjornsson, David B. Beck, P. Dane Witmer, Nara Sobreira, Elizabeth Wohler, John A. Chiorini, The American Genome Center, Clifton L. Dalgard, NIH Intramural Sequencing Center, Daniel L. Kastner, and Ivona Aksentijevich
- Subjects
Adult ,Male ,0301 basic medicine ,Adolescent ,Genotype ,Adenosine Deaminase ,Immunology ,Inheritance Patterns ,Penetrance ,Biology ,Article ,DNA sequencing ,Young Adult ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Exome Sequencing ,Gene duplication ,medicine ,Humans ,Immunology and Allergy ,Genetic Predisposition to Disease ,Multiplex ligation-dependent probe amplification ,Allele ,Child ,Genetic Association Studies ,Exome sequencing ,Genetic testing ,Genetics ,Sanger sequencing ,medicine.diagnostic_test ,Brain ,Genetic Variation ,Sequence Analysis, DNA ,Pedigree ,Enzyme Activation ,Phenotype ,030104 developmental biology ,Child, Preschool ,Mutation ,symbols ,Intercellular Signaling Peptides and Proteins ,Female ,030215 immunology - Abstract
PURPOSE: Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disorder that manifests with fever, early-onset vasculitis, strokes, and hematologic dysfunction. This study aimed to identify disease-causing variants by conventional Sanger and whole exome sequencing in two families suspected to have DADA2 and non-confirmatory genotypes. ADA2 enzymatic assay confirmed the clinical diagnosis of DADA2. Molecular diagnosis was important to accurately identify other family members at risk. METHODS: We used a variety of sequencing technologies, ADA2 enzymatic testing, and molecular methods including qRT-PCR, MLPA. RESULTS: Exome sequencing identified heterozygosity for the known pathogenic variant ADA2: c.1358A>G, p.Y453C in a 14-year-old female with a history of ischemic strokes, livedo, and vasculitis. No second pathogenic variant could be identified. ADA2 enzymatic testing in combination with quantitative RT-PCR suggested a loss-of-function allele. Subsequent genome sequencing identified a canonical splice site variant, c.−47+2T>C, within the 5’UTR of ADA2. Two of her unaffected siblings were found to carry the same two pathogenic variants. A homozygous 800bp duplication comprising exon 7 of ADA2 was identified in a 5-year-old female with features consistent with Diamond-Blackfan anemia (DBA). The duplication was missed by Sanger sequencing of ADA2, chromosomal microarray, and exome sequencing but was detected by MLPA in combination with long-read PCR sequencing. The exon 7 duplication was also identified in her non-symptomatic father and younger sister. CONCLUSIONS: ADA2 pathogenic variants may not be detected by conventional sequencing and genetic testing and may require the incorporation of additional diagnostic methods. A definitive molecular diagnosis is crucial for all family members to make informed treatment decisions.
- Published
- 2020
26. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS
- Author
-
Mihai G. Netea, David B. Beck, A. Elizabeth Hak, Huub P.J. Willems, Pieter van Paassen, Caspar I van der Made, Marielle E. van Gijn, Frank L. van de Veerdonk, Arjan J. Kwakernaak, Lars T. van der Veken, Marloes W Heijstek, Annemiek Hoogstins, Alexander Hoischen, Ruud G. L. de Sévaux, Helen L. Leavis, Paul L A van Daele, Abraham Rutgers, Judith Potjewijd, Annet Simons, Translational Immunology Groningen (TRIGR), Immunology, MUMC+: MA Nefrologie (9), Interne Geneeskunde, and RS: Carim - B02 Vascular aspects thrombosis and Haemostasis
- Subjects
Adult ,Male ,0301 basic medicine ,medicine.medical_specialty ,Myeloid ,somatic variants ,Interstitial nephritis ,Immunology ,Perforation (oil well) ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Ubiquitin-Activating Enzymes ,MOSAICISM ,03 medical and health sciences ,chemistry.chemical_compound ,Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2] ,0302 clinical medicine ,Tocilizumab ,All institutes and research themes of the Radboud University Medical Center ,Internal medicine ,medicine ,Humans ,VEXAS ,Immunology and Allergy ,Age of Onset ,Aged ,Netherlands ,Retrospective Studies ,UBA1 ,030203 arthritis & rheumatology ,IMMUNODEFICIENCY ,Cytopenia ,IDENTIFICATION ,business.industry ,Hereditary Autoinflammatory Diseases ,Skin Diseases, Genetic ,Middle Aged ,autoinflammation ,medicine.disease ,Transplantation ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Myelodysplastic Syndromes ,Mutation ,Differential diagnosis ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,Vasculitis - Abstract
Background: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS. Objective: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease. Methods: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS. Results: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%. Conclusion: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation. (J Allergy Clin Immunol 2022;149:432-9.)
- Published
- 2022
27. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population
- Author
-
David B. Beck, Dale L. Bodian, Vandan Shah, Uyenlinh L. Mirshahi, Jung Kim, Yi Ding, Samuel J. Magaziner, Natasha T. Strande, Anna Cantor, Jeremy S. Haley, Adam Cook, Wesley Hill, Alan L. Schwartz, Peter C. Grayson, Marcela A. Ferrada, Daniel L. Kastner, David J. Carey, and Douglas R. Stewart
- Subjects
General Medicine - Abstract
ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.ObjectiveTo determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, Setting, and ParticipantsThis retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.ExposuresExome sequencing was performed.Main Outcomes and MeasuresOutcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.ResultsIn 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).Conclusions and RelevanceThis study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
- Published
- 2023
28. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease
- Author
-
Natasha Silke, Manfred Boehm, Amanda K. Ombrello, Ivona Aksentijevich, Deborah L. Stone, Tina Romeo, Marco J Herold, Laurens Wachsmuth, Christine Biben, Beverly K. Barham, Lin Liu, Andrew J. Gross, Sergio D. Rosenzweig, Patrycja Hoffmann, Natalia Sampaio Moura, Gustavo Gutierrez-Cruz, Daniel L. Kastner, Steven E. Boyden, Kristien J. M. Zaal, Anne K. Voss, Holly Anderton, Anne Jones, Hongying Wang, Tobias Kratina, John Silke, Michael J. Lenardo, James C. Mullikin, Kate E. Lawlor, David B. Beck, Mark D. McKenzie, Amanda Light, Anthony K. Shum, Jae Jin Chae, Massimo Gadina, Qing Zhou, Diep Chau, Gineth Pinto-Patarroyo, Hirotsugu Oda, Geryl Wood, Mary Blake, Nima Etemadi, Kristy Shield-Artin, Edwin D. Hawkins, Monique Stoffels, Cathrine Hall, Dan Yang, Wanxia Li Tsai, Hye Sun Kuehn, Natalia I. Dmitrieva, Seth L. Masters, Lixin Zheng, Andrew J. Kueh, Manolis Pasparakis, and Najoua Lalaoui
- Subjects
Male ,0301 basic medicine ,Programmed cell death ,General Science & Technology ,Knockout ,Necroptosis ,Caspase 3 ,Inflammation ,Biology ,Inbred C57BL ,Caspase 8 ,Article ,Mice ,03 medical and health sciences ,RIPK1 ,0302 clinical medicine ,medicine ,Animals ,Humans ,Kinase activity ,Mice, Knockout ,Multidisciplinary ,Hereditary Autoinflammatory Diseases ,MAP Kinase Kinase Kinases ,medicine.disease ,Pedigree ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Receptor-Interacting Protein Serine-Threonine Kinases ,030220 oncology & carcinogenesis ,Mutation ,Female ,medicine.symptom ,Periodic fever syndrome - Abstract
Receptor Interacting Protein Kinase 1 (RIPK1) is a key regulator of innate immune signalling pathways. To ensure an optimal inflammatory response, RIPK1 is post-translationally regulated by well characterised ubiquitylation and phosphorylation events, as well as caspase-8 mediated cleavage1–7. The physiological relevance of this cleavage remains unclear, though it is believed to inhibit activation of RIPK3 and necroptosis8. Here we show that heterozygous missense mutations p.D324N, p.D324H and p.D324Y prevent caspase cleavage of RIPK1 in humans and result in early-onset periodic fever episodes and severe intermittent lymphadenopathy, a condition we designate ‘Cleavage-resistant RIPK1-Induced Autoinflammatory’ (CRIA) syndrome. To define the mechanism for this disease we generated a cleavage-resistant Ripk1D325A mutant mouse strain. While Ripk1-/- mice die postnatally from systemic inflammation, Ripk1D325A/D325A mice died during embryogenesis. Embryonic lethality was completely prevented by combined loss of Casp8 and Ripk3 but not by loss of Ripk3 or Mlkl alone. Loss of RIPK1 kinase activity also prevented Ripk1D325A/D325A embryonic lethality, however the mice died before weaning from multi organ inflammation in a RIPK3 dependent manner. Consistently, Ripk1D325A/D325A and Ripk1D325A/+ cells were hypersensitive to RIPK3 dependent TNF-induced apoptosis and necroptosis. Heterozygous Ripk1D325A/+ mice were viable and grossly normal, but were hyper-responsive to inflammatory stimuli in vivo. Our results demonstrate the importance of caspase-mediated RIPK1 cleavage during embryonic development and show that caspase cleavage of RIPK1 not only inhibits necroptosis but maintains inflammatory homeostasis throughout life.
- Published
- 2019
29. Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
- Author
-
Trudie Cottrell, Jacques C. Giltay, Richard H. van Jaarsveld, Elles M. J. Boon, Roger E. Stevenson, Michael A. Levy, Kimberly F. Doheny, Bekim Sadikovic, G. Bradley Schaefer, Roberto Bonasio, Muhammad Ansar, Vinodh Narayanan, Mieke M. van Haelst, Jill A. Fahrner, Marleen Simon, David B. Beck, Claudia A. L. Ruivenkamp, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marie-Christine Nougues, Hannah W. Moore, Marielle Alders, Renske Oegema, M. Mahdi Motazacker, Kay Metcalfe, Cyril Mignot, Jennifer Kerkhof, Gijs W. E. Santen, Jessica Bos, Sofia Douzgou, Siddharth Banka, Keri Ramsey, Boris Keren, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ANS - Complex Trait Genetics, AR&D - Amsterdam Reproduction & Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)
- Subjects
Genetics ,Epigenomics ,DNA methylation ,Neurodevelopmental disorders ,Diagnostic markers ,QH426-470 ,Biology ,medicine.disease ,Phenotype ,Genome ,Article ,Neurodevelopmental disorder ,DNA demethylation ,CpG site ,medicine ,DNMT1 ,Medicine ,Epigenetics ,Author Correction ,Molecular Biology ,Genetics (clinical) - Abstract
TET3 encodes an essential dioxygenase involved in epigenetic regulation through DNA demethylation. TET3 deficiency, or Beck-Fahrner syndrome (BEFAHRS; MIM: 618798), is a recently described neurodevelopmental disorder of the DNA demethylation machinery with a nonspecific phenotype resembling other chromatin-modifying disorders, but inconsistent variant types and inheritance patterns pose diagnostic challenges. Given TET3’s direct role in regulating 5-methylcytosine and recent identification of syndrome-specific DNA methylation profiles, we analyzed genome-wide DNA methylation in whole blood of TET3-deficient individuals and identified an episignature that distinguishes affected and unaffected individuals and those with mono-allelic and bi-allelic pathogenic variants. Validation and testing of the episignature correctly categorized known TET3 variants and determined pathogenicity of variants of uncertain significance. Clinical utility was demonstrated when the episignature alone identified an affected individual from over 1000 undiagnosed cases and was confirmed upon distinguishing TET3-deficient individuals from those with 46 other disorders. The TET3-deficient signature - and the signature resulting from activating mutations in DNMT1 which normally opposes TET3 - are characterized by hypermethylation, which for BEFAHRS involves CpG sites that may be biologically relevant. This work expands the role of epi-phenotyping in molecular diagnosis and reveals genome-wide DNA methylation profiling as a quantitative, functional readout for characterization of this new biochemical category of disease.
- Published
- 2021
30. Author Correction: Deficiency of TET3 leads to a genome-wide DNA hypermethylation episignature in human whole blood
- Author
-
Renske Oegema, Vinodh Narayanan, Marleen Simon, Trudie Cottrell, Marie-Christine Nougues, Mieke M. van Haelst, Gijs W. E. Santen, Roger E. Stevenson, Keri Ramsey, Kay Metcalfe, Jacques C. Giltay, Sivagamy Sithambaram, Teresa Romeo Luperchio, Leandros Boukas, Marielle Alders, Hannah W. Moore, Claudia A. L. Ruivenkamp, Jessica Bos, Richard H. van Jaarsveld, Jill A. Fahrner, David B. Beck, Sofia Douzgou, Jennifer Kerkhof, Muhammad Ansar, Michael A. Levy, G. Bradley Schaefer, Siddharth Banka, Roberto Bonasio, Kimberly F. Doheny, M. Mahdi Motazacker, Cyril Mignot, Elles M. J. Boon, Boris Keren, and Bekim Sadikovic
- Subjects
Genetics ,Medicine ,Dna hypermethylation ,QH426-470 ,Biology ,Molecular Biology ,Genome ,Genetics (clinical) ,Whole blood - Published
- 2021
31. Incidence, Clinical Associations, and Co-Mutation Patterns of UBA1 Mutations in MDS
- Author
-
Maria Sirenko, Elsa Bernard, David B. Beck, Maria Creignou, Dylan Domenico, Andrea Farina, Juan E Arango, Olivier Kosmider, Robert P. Hasserjian, Martin Jadersten, Ulrich Germing, Guillermo Sanz, Arjan A. van de Loosdrecht, Matilde Y Follo, Felicitas R. Thol, Lurdes Zamora, Ronald Feitosa Pinheiro, Andrea Pellagatti, Harold K. Elias, Detlef Haase, Christina Ganster, Lionel Ades, Magnus Tobiasson, Laura Palomo, Matteo G. Della Porta, Kety Huberman, Pierre Fenaux, Monika Belickova, Michael R. Savona, Virginia M. Klimek, Fabio Pires de Souza Santos, Jacqueline Boultwood, Ioannis Kotsianidis, Valeria Santini, Francesc Solé, Uwe Platzbecker, Michael Heuser, Peter Valent, Carlo Finelli, Maria Teresa Voso, Lee-Yung Shih, Seishi Ogawa, Michaela Fontenay, Joop H. Jansen, Jose Cervera, Benjamin L. Ebert, Rafael Bejar, Peter L Greenberg, Norbert Gattermann, Luca Malcovati, Mario Cazzola, Eva Hellström-Lindberg, and Elli Papaemmanuil
- Subjects
Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
32. VEXAS Syndrome: A Case Series From a Single-Center Cohort of Italian Patients With Vasculitis
- Author
-
Elena Galli, Luigi Boiardi, Peter C. Grayson, Nicholas Balanda, Chiara Marvisi, Nicolò Pipitone, David B. Beck, Orsola Bonanno, Carlo Salvarani, Enrico Farnetti, Francesco Muratore, Davide Nicoli, Piera Zaldini, Paola Castrignanò, and Rosina Longo
- Subjects
Male ,Vasculitis ,medicine.medical_specialty ,Immunology ,Ubiquitin-Activating Enzymes ,Single Center ,Antibodies, Antineutrophil Cytoplasmic ,Rheumatology ,Internal medicine ,medicine ,Immunology and Allergy ,Humans ,Retrospective Studies ,Inflammation ,business.industry ,medicine.disease ,Autoinflammatory Syndrome ,medicine.anatomical_structure ,Concomitant ,Myelodysplastic Syndromes ,Cohort ,Mutation ,Who criteria ,Bone marrow ,business ,Systemic vasculitis - Abstract
To identify patients with VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) from a single-center cohort of Italian patients with vasculitis, using a clinically oriented phenotype-first approach.We retrospectively reviewed the clinical records of 147 consecutive male patients followed up in our vasculitis clinic from 2013 to date. All patients with a diagnosis of vasculitis and treatment-resistant manifestations of inflammation, persistently elevated inflammation markers, and hematologic abnormalities were identified. Bone marrow aspirates were examined for the presence of vacuoles. Sequencing of ubiquitin-activating enzyme E1 (UBA-1) was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue.Seven patients with vasculitis and concomitant features of VEXAS syndrome were identified. A final diagnosis of VEXAS syndrome was made in 3 of the 5 patients who underwent sequencing of UBA-1 (diagnosis was made postmortem for 1 patient). In all 3 patients, examination of the bone marrow aspirate revealed vacuoles characteristic of VEXAS syndrome, and all 3 patients met the definitive World Health Organization criteria for myelodysplastic syndrome. Cytogenetic analysis showed normal karyotypes in all 3 patients.To our knowledge, this is the first report of VEXAS syndrome associated with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Our data emphasize the need to consider VEXAS syndrome when evaluating patients with various forms of systemic vasculitis. The novel association between VEXAS syndrome and ANCA-associated vasculitis reported herein warrants further investigation.
- Published
- 2021
33. Phenotypic expansion of the BPTF-related neurodevelopmental disorder with dysmorphic facies and distal limb anomalies
- Author
-
Dusit Adstamongkonkul, Inger Lise Mero, Morten Buch Engelund, Elena Gardella, Deepali N. Shinde, Felix Boschann, Ingrid Cristian, Irma van de Beek, Johanna C. Acosta Guio, Corinna Stoltenburg, Diana Moskal-Jasińska, Anna C.E. Hurst, Alina T. Midro, Linda Zuurbier, Kristine Lossius, Kevin E. Glinton, Ariel Brautbar, Cyril Mignot, Lindsay B. Henderson, Paul Vos, Carole Brewer, Oliver Puk, Alan Donaldson, Eugeniusz Tarasów, David B. Beck, Julian A. Martinez, Arie van Haeringen, Pawel Stankiewicz, Yline Capri, Amélie Piton, Yaping Yang, Louise Amlie-Wolf, Kevin M. Bowling, Devon Haynes, Saskia Koene, Alberto Gómez, Boris Keren, Margherita Furlan, Karen W. Gripp, Pernille Mathiesen Tørring, Ignacio Briceño, Oskar Schnappauf, Aditi Shah Parikh, Rikke S. Møller, Phillis Lakeman, Beata Stasiewicz-Jarocka, Allan Bayat, Rebecca Signer, and Human Genetics
- Subjects
Adult ,Male ,0301 basic medicine ,Microcephaly ,Adolescent ,Developmental Disabilities ,Haploinsufficiency ,Postnatal microcephaly ,030105 genetics & heredity ,Bioinformatics ,chromatin remodeling ,Young Adult ,03 medical and health sciences ,Epilepsy ,Neurodevelopmental disorder ,Intellectual Disability ,Intellectual disability ,Genetics ,Humans ,Medicine ,Abnormalities, Multiple ,Language Development Disorders ,microcephaly ,Child ,Genetics (clinical) ,business.industry ,Facies ,Infant ,Original Articles ,Middle Aged ,Chromatin Assembly and Disassembly ,medicine.disease ,Phenotype ,030104 developmental biology ,Neurodevelopmental Disorders ,PHD finger ,Child, Preschool ,Speech delay ,epilepsy ,Female ,Original Article ,Chromosome Deletion ,medicine.symptom ,business ,Transcription Factors - Abstract
Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL), defined primarily by developmental delay/intellectual disability, speech delay, postnatal microcephaly, and dysmorphic features, is a syndrome resulting from heterozygous variants in the dosage‐sensitive bromodomain PHD finger chromatin remodeler transcription factor BPTF gene. To date, only 11 individuals with NEDDFL due to de novo BPTF variants have been described. To expand the NEDDFL phenotypic spectrum, we describe the clinical features in 25 novel individuals with 20 distinct, clinically relevant variants in BPTF, including four individuals with inherited changes in BPTF. In addition to the previously described features, individuals in this cohort exhibited mild brain abnormalities, seizures, scoliosis, and a variety of ophthalmologic complications. These results further support the broad and multi‐faceted complications due to haploinsufficiency of BPTF.
- Published
- 2021
34. The use of leukocytes’ secretome to individually target biological therapy in autoimmune arthritis: a case report
- Author
-
Marie-Pier Longchamps, Philippe A. Tessier, Patrice E. Poubelle, Martin Pelletier, David B. Beck, Natalia Sampaio Moura, Nathalie Pagé, and Ivona Aksentijevich
- Subjects
0301 basic medicine ,Medicine (miscellaneous) ,Arthritis ,Case Report ,03 medical and health sciences ,Psoriatic arthritis ,chemistry.chemical_compound ,0302 clinical medicine ,Tocilizumab ,Prednisone ,Ustekinumab ,medicine ,Adalimumab ,Leukocytes ,Secretome ,lcsh:R5-920 ,business.industry ,Interleukin-6 ,Abatacept ,Hydroxychloroquine ,medicine.disease ,Personalized medicine ,Biologic agents ,030104 developmental biology ,chemistry ,TRAF3IP2 ,030220 oncology & carcinogenesis ,Immunology ,Molecular Medicine ,business ,lcsh:Medicine (General) ,TRAF6 ,medicine.drug - Abstract
Background Biological agents have allowed remarkable improvement in controlling autoimmune arthropathies, although none of the numerous biologics readily available represent a universal treatment standard. Moreover, classical and genetic predictors are currently unsatisfactory to predict individual response to a biologic, and the best treatment selection is still based on a trial-and-error approach. Here, we report a clinical case demonstrating the usefulness of examining the leukocytes’ secretome of patients. We set up and standardized a protocol that examines a patient’s immune responses to establish the secretome of the blood mononuclear leukocytes and personalize the biotherapy. Case presentation A 24-year-old woman was diagnosed with active early rheumatoid arthritis. The initial treatment regimen (prednisone, methotrexate, hydroxychloroquine, naproxen) was inefficient, as well as the anti-TNF adalimumab. The diagnosis was revised as possible rheumatoid arthritis-like psoriatic arthritis and adalimumab was replaced by abatacept (IgG1 Fc-CTLA-4) to no avail. Five years later, abatacept was replaced by the anti-IL-12/IL-23 ustekinumab with no objective control over the symptoms. The patient was thus enrolled in a prospective study based on the quantification of cytokines secreted by peripheral blood leukocytes stimulated with well-known immune activators of pattern recognition receptors and cytokine signalling. The results of this study revealed that plasma concentrations of cytokines were similar between the patient and healthy donors. In comparison to leukocytes from healthy donors, the patient’s secretome showed a unique overproduction of IL-6. The anti-IL-6 receptor tocilizumab was, therefore, administered with a rapid improvement of her active psoriatic arthritis that remained dependent on low prednisone dosage. Clinical parameters progressively returned to normal levels and her quality of life was greatly improved, despite the major delay to begin the present personalized treatment. Conclusions An efficient way to effectively treat patients with complex autoimmune arthropathies, and avoid irreversible disability, is to know their leukocytes’ secretome to identify abnormally secreted cytokines and personalize their biotherapy, as exemplified by this case report.
- Published
- 2019
35. Clinical Heterogeneity of the VEXAS Syndrome: A Case Series
- Author
-
Matthew J, Koster, Taxiarchis, Kourelis, Kaaren K, Reichard, Tanaz A, Kermani, David B, Beck, Daniela Ospina, Cardona, Matthew J, Samec, Abhishek A, Mangaonkar, Kebede H, Begna, C Christopher, Hook, Jennifer L, Oliveira, Samih H, Nasr, Benedict K, Tiong, Mrinal M, Patnaik, Michelle M, Burke, Clement J, Michet, and Kenneth J, Warrington
- Subjects
Erythroid Precursor Cells ,Inflammation ,Male ,Vasculitis ,Myelodysplastic Syndromes ,Mutation ,Vacuoles ,Genetic Diseases, Inborn ,Humans ,Genetic Diseases, X-Linked ,Myeloid Cells ,Ubiquitin-Activating Enzymes ,Aged - Abstract
The objective of this study is to describe the clinical features and outcomes of patients with the newly defined vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome. Nine men with somatic mutations in the UBA1 gene were identified; the most frequent variant was p.Met41Thr (7 of 9, 78%). The median age at VEXAS diagnosis was 74 (67, 76.5) years, and patients had a median duration of symptoms for 4 years before diagnosis. Refractory constitutional symptoms (88%), ear and nose chondritis (55%), and inflammatory arthritis (55%) were common clinical features. Vasculitis was noted in 44%. All patients had significantly elevated inflammatory markers and macrocytic anemia. Thrombocytopenia was present in 66% at diagnosis of VEXAS. Eight patients had bone marrow biopsies performed. All bone marrows were hypercellular, and there was vacuolization of the erythroid (100%) or myeloid precursors (75%). Glucocorticoids attenuated symptoms at prednisone doses ≥20 mg per day, but no other immunosuppressive agent showed consistent long-term control of disease. One patient with coexisting plasma-cell myeloma received plasma-cell-directed therapy with improvement of the inflammatory response, which is a novel finding. In conclusion, VEXAS syndrome is a clinically heterogeneous, treatment-refractory inflammatory condition caused by somatic mutation of the UBA1 gene. Patients often present with overlapping rheumatologic manifestations and persistent hematologic abnormalities. As such, internists and subspecialists, including pathologists, should be aware of this condition to avert diagnostic delay, now that the etiology of this syndrome is known.
- Published
- 2021
36. Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: fevers, myalgia, arthralgia, auricular chondritis, and erythema nodosum
- Author
-
Luke Y.C. Chen, David B. Beck, Natasha Dehghan, Jan P. Dutz, Krista M Marcon, and Tony Sedlic
- Subjects
myalgia ,Male ,2019-20 coronavirus outbreak ,medicine.medical_specialty ,Fever ,Somatic cell ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Vacuole ,Ubiquitin-Activating Enzymes ,Erythema Nodosum ,Medicine ,Humans ,Chondritis ,Polychondritis, Relapsing ,chemistry.chemical_classification ,Erythema nodosum ,Inflammation ,business.industry ,General Medicine ,Myalgia ,Middle Aged ,medicine.disease ,Dermatology ,Arthralgia ,Enzyme ,chemistry ,Mutation ,Vacuoles ,Prednisone ,medicine.symptom ,business - Published
- 2021
37. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation
- Author
-
Sander Pajusalu, Inga Talvik, Raymond Y. Wang, Daniel L. Kastner, Achim Werner, Mohammed Abul Basar, Precilla D'Souza, Katrin Õunap, Yutaka Nishimura, Johji Inazawa, Ken Saida, Ellen Macnamara, David B. Beck, Anthony J. Asmar, Kristin W. Barañano, Hirotsugu Oda, Marlies Kempers, Weiyi Mu, Naomichi Matsumoto, Joann Bodurtha, Tomoki Kosho, Joyce J. Thompson, Pedro P. Rocha, Ivona Aksentijevich, Apratim Mitra, Magdalena Walkiewicz, Tomoko Tamada, Ryan K. Dale, Satoshi Okada, Daniela Tiaki Uehara, Noriko Miyake, and Cynthia J. Tifft
- Subjects
ARID1A ,Biochemistry ,Chromatin remodeling ,03 medical and health sciences ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,Ubiquitin ,Gene expression ,Genetics ,Humans ,Enhancer ,Research Articles ,030304 developmental biology ,0303 health sciences ,Multidisciplinary ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,Histone deacetylase 2 ,Ubiquitination ,SciAdv r-articles ,Human Genetics ,Genomics ,Phenotype ,Chromatin ,Cell biology ,biology.protein ,030217 neurology & neurosurgery ,Research Article ,Signal Transduction - Abstract
Disease-causing mutations in a linkage-specific deubiquitylase provide insights into chromatin remodeling during embryogenesis., Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage–specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency–induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.
- Published
- 2021
38. Somatic Mutations in
- Author
-
David B, Beck, Marcela A, Ferrada, Keith A, Sikora, Amanda K, Ombrello, Jason C, Collins, Wuhong, Pei, Nicholas, Balanda, Daron L, Ross, Daniela, Ospina Cardona, Zhijie, Wu, Bhavisha, Patel, Kalpana, Manthiram, Emma M, Groarke, Fernanda, Gutierrez-Rodrigues, Patrycja, Hoffmann, Sofia, Rosenzweig, Shuichiro, Nakabo, Laura W, Dillon, Christopher S, Hourigan, Wanxia L, Tsai, Sarthak, Gupta, Carmelo, Carmona-Rivera, Anthony J, Asmar, Lisha, Xu, Hirotsugu, Oda, Wendy, Goodspeed, Karyl S, Barron, Michele, Nehrebecky, Anne, Jones, Ryan S, Laird, Natalie, Deuitch, Dorota, Rowczenio, Emily, Rominger, Kristina V, Wells, Chyi-Chia R, Lee, Weixin, Wang, Megan, Trick, James, Mullikin, Gustaf, Wigerblad, Stephen, Brooks, Stefania, Dell'Orso, Zuoming, Deng, Jae J, Chae, Alina, Dulau-Florea, May C V, Malicdan, Danica, Novacic, Robert A, Colbert, Mariana J, Kaplan, Massimo, Gadina, Sinisa, Savic, Helen J, Lachmann, Mones, Abu-Asab, Benjamin D, Solomon, Kyle, Retterer, William A, Gahl, Shawn M, Burgess, Ivona, Aksentijevich, Neal S, Young, Katherine R, Calvo, Achim, Werner, Daniel L, Kastner, and Peter C, Grayson
- Subjects
Aged, 80 and over ,Inflammation ,Male ,Genotype ,Giant Cell Arteritis ,Immunoblotting ,Mutation, Missense ,Genetic Diseases, X-Linked ,Sequence Analysis, DNA ,Syndrome ,Ubiquitin-Activating Enzymes ,Middle Aged ,Sweet Syndrome ,Article ,Autoimmune Diseases ,Polyarteritis Nodosa ,Myelodysplastic Syndromes ,Cytokines ,Humans ,Exome ,Polychondritis, Relapsing ,Age of Onset ,Multiple Myeloma ,Aged - Abstract
Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders.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.We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation. (The geneUsing 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.).
- Published
- 2020
39. Control of craniofacial and brain development by Cullin3-RING ubiquitin ligases: Lessons from human disease genetics
- Author
-
Achim Werner, David B. Beck, and Anthony J. Asmar
- Subjects
0301 basic medicine ,Cell type ,Brain development ,Cellular differentiation ,Ubiquitin-Protein Ligases ,Biology ,03 medical and health sciences ,0302 clinical medicine ,Human disease ,Ubiquitin ,Animals ,Humans ,Disease ,Craniofacial ,Induced pluripotent stem cell ,Genetics ,Skull ,Brain ,Cell Biology ,Cullin Proteins ,030104 developmental biology ,030220 oncology & carcinogenesis ,Face ,biology.protein ,Identification (biology) - Abstract
Metazoan development relies on intricate cell differentiation, communication, and migration pathways, which ensure proper formation of specialized cell types, tissues, and organs. These pathways are crucially controlled by ubiquitylation, a reversible post-translational modification that regulates the stability, activity, localization, or interaction landscape of substrate proteins. Specificity of ubiquitylation is ensured by E3 ligases, which bind substrates and co-operate with E1 and E2 enzymes to mediate ubiquitin transfer. Cullin3-RING ligases (CRL3s) are a large class of multi-subunit E3s that have emerged as important regulators of cell differentiation and development. In particular, recent evidence from human disease genetics, animal models, and mechanistic studies have established their involvement in the control of craniofacial and brain development. Here, we summarize regulatory principles of CRL3 assembly, substrate recruitment, and ubiquitylation that allow this class of E3s to fulfill their manifold functions in development. We further review our current mechanistic understanding of how specific CRL3 complexes orchestrate neuroectodermal differentiation and highlight diseases associated with their dysregulation. Based on evidence from human disease genetics, we propose that other unknown CRL3 complexes must help coordinate craniofacial and brain development and discuss how combining emerging strategies from the field of disease gene discovery with biochemical and human pluripotent stem cell approaches will likely facilitate their identification.
- Published
- 2020
40. The Role of Host Genetic Factors in Coronavirus Susceptibility: Review of Animal and Systematic Review of Human Literature
- Author
-
Derek A. T. Cummings, Priya Duggal, Marissa LoPresti, David B. Beck, and Benjamin D. Solomon
- Subjects
0301 basic medicine ,Coronavirus disease 2019 (COVID-19) ,Key genes ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Pneumonia, Viral ,030106 microbiology ,coronavirus ,Biology ,medicine.disease_cause ,Article ,Betacoronavirus ,03 medical and health sciences ,Species Specificity ,Pandemic ,medicine ,Genetics ,Animals ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,Allele ,Pandemics ,Gene ,Genetics (clinical) ,Disease Reservoirs ,Coronavirus ,Human studies ,SARS-CoV-2 ,Host (biology) ,host genetic factors ,COVID-19 ,030104 developmental biology ,Receptors, Virus ,Animal studies ,Coronavirus Infections - Abstract
Summary The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies. We identified 1,832 articles of potential relevance. Seventy-five involved human host genetic factors, 36 of which involved analysis of specific genes or loci; aside from one meta-analysis, all were candidate-driven studies, typically investigating small numbers of research subjects and loci. Three additional case reports were described. Multiple significant loci were identified, including 16 related to susceptibility (seven of which identified protective alleles) and 16 related to outcomes (three of which identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Among other studies, 30 involved both human and non-human host genetic factors related to coronavirus, 178 involved study of non-human (animal) host genetic factors related to coronavirus, and 984 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis. Previous human studies have been limited by issues that may be less impactful now, including low numbers of eligible participants and limited availability of advanced genomic methods; however, these may raise additional considerations. We outline key genes and loci from animal and human host genetic studies that may bear investigation in the study of COVID-19. We also discuss how previous studies may direct current lines of inquiry., The SARS-CoV-2 pandemic raises many scientific and clinical questions. These include how host genetic factors affect disease susceptibility and pathogenesis. New work is emerging related to SARS-CoV-2; previous work has been conducted on other coronaviruses that affect different species. We reviewed the literature on host genetic factors related to coronaviruses, systematically focusing on human studies. We identified 1,832 articles of potential relevance. Seventy-five involved human host genetic factors, 36 of which involved analysis of specific genes or loci; aside from one meta-analysis, all were candidate-driven studies, typically investigating small numbers of research subjects and loci. Three additional case reports were described. Multiple significant loci were identified, including 16 related to susceptibility (seven of which identified protective alleles) and 16 related to outcomes (three of which identified protective alleles). The types of cases and controls used varied considerably; four studies used traditional replication/validation cohorts. Among other studies, 30 involved both human and non-human host genetic factors related to coronavirus, 178 involved study of non-human (animal) host genetic factors related to coronavirus, and 984 involved study of non-genetic host factors related to coronavirus, including involving immunopathogenesis. Previous human studies have been limited by issues that may be less impactful now, including low numbers of eligible participants and limited availability of advanced genomic methods; however, these may raise additional considerations. We outline key genes and loci from animal and human host genetic studies that may bear investigation in the study of COVID-19. We also discuss how previous studies may direct current lines of inquiry.
- Published
- 2020
- Full Text
- View/download PDF
41. Regulation of human development by ubiquitin chain editing of chromatin remodelers
- Author
-
Precilla D'Souza, Anthony J. Asmar, Daniela Tiaki Uehara, Weiyi Mu, Marlies Kempers, Tomoki Kosho, Ryan K. Dale, David B. Beck, Pedro P. Rocha, Cynthia J. Tifft, Naomichi Matsumoto, Ellen Macnamara, Apratim Mitra, Satoshi Okada, Noriko Miyake, Raymond Y. Wang, Ken Saida, Daniel L. Kastner, Magdalena Walkiewicz, Achim Werner, Yutaka Nishimura, Joann Bodurtha, Joyce J. Thompson, Johi Inazawa, Ivona Aksentijevich, Hirotsugu Oda, Mohammed Abul Basar, and Kristin W. Barañano
- Subjects
Ubiquitin ,biology ,ARID1A ,biology.protein ,Neural crest ,Enhancer ,Induced pluripotent stem cell ,Embryonic stem cell ,Chromatin remodeling ,Cell biology ,Chromatin - Abstract
Embryonic development occurs through commitment of pluripotent stem cells to differentiation programs that require highly coordinated changes in gene expression. Chromatin remodeling of gene regulatory elements is a critical component of how such changes are achieved. While many factors controlling chromatin dynamics are known, mechanisms of how different chromatin regulators are orchestrated during development are not well understood. Here, we describe LINKED (LINKage-specific-deubiquitylation-deficiency-induced Embryonic Defects) syndrome, a novel multiple congenital anomaly disorder caused by hypomorphic hemizygous missense variants in the deubiquitylase OTUD5/DUBA. Studying LINKED mutations in vitro, in mouse, and in models of neuroectodermal differentiation of human pluripotent stem cells, we uncover a novel regulatory circuit that coordinates chromatin remodeling pathways during early differentiation. We show that the K48-linkage-specific deubiquitylation activity of OTUD5 is essential for murine and human development and, if reduced, leads to aberrant cell-fate specification. OTUD5 controls differentiation through preventing the degradation of multiple chromatin regulators including ARID1A/B and HDAC2, mutation of which underlie developmental syndromes that exhibit phenotypic overlap with LINKED patients. Accordingly, loss of OTUD5 during early differentiation leads to less accessible chromatin at neural and neural crest enhancers and thus aberrant rewiring of gene expression networks. Our work identifies a novel mechanistic link between phenotypically related developmental disorders and an essential function for linkagespecific ubiquitin editing of substrate groups (i.e. chromatin remodeling complexes) during early cellfate decisions – a regulatory concept, we predict to be a general feature of embryonic development.
- Published
- 2020
42. Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction
- Author
-
Kristina Cusmano-Ozog, David B. Beck, Nickie Andescavage, and Eyby Leon
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Mitochondrial disease ,Sengers syndrome ,030105 genetics & heredity ,Congenital lactic acidosis ,Chorioamnionitis ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,AGK ,Original Research ,business.industry ,Hypertrophic cardiomyopathy ,General Medicine ,medicine.disease ,Bilateral Cataracts ,acylglycerol kinase ,Lactic acidosis ,Severe lactic acidosis ,business ,Acylglycerol kinase ,030217 neurology & neurosurgery - Abstract
Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophic cardiomyopathy and bilateral cataracts. We present here a case of neonatal demise, within the first day of life, who initially presented with severe lactic acidosis, with evidence of both chorioamnionitis and cardiogenic shock. Initial metabolic labs demonstrated a severe lactic acidosis prompting genetic testing which revealed a homozygous pathogenic variant for Sengers syndrome in AGK, c.979A > T; p.K327*. In addition to the canonical features of Sengers syndrome, our patient is the first reported case with liver dysfunction extending the phenotypic spectrum both in terms of severity and complications. This case also highlights the importance of maintaining a broad differential for congenital lactic acidosis.
- Published
- 2018
43. Clinical Efficacy of JAK Inhibitors in Patients with Vexas Syndrome: A Multicenter Retrospective Study
- Author
-
Pierre Fenaux, Marcela A. Ferrada, Fiorenza Barraco, Kenneth J. Warrington, Mathieu Gerfaud-Valentin, Pierre Sujobert, Pierre Hirsch, Lionel Galicier, Maël Heiblig, Guillaume Le Guenno, Bhavisha A Patel, Matthew J. Koster, Thomas Barba, Gaelle Fossard, Henrique Coelho, Peter C. Grayson, Anne Blandine Boutin, Adrien Bigot, David B. Beck, Arsène Mekinian, Tanaz A. Kermani, Guillaume Vial, Yvan Jamilloux, and Boris Bienvenu
- Subjects
medicine.medical_specialty ,business.industry ,Internal medicine ,Immunology ,medicine ,Retrospective cohort study ,In patient ,Cell Biology ,Hematology ,Clinical efficacy ,business ,Biochemistry - Abstract
Background VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is due to a somatically acquired mutation of the E1-ubiquitin ligase UBA1, leading to the expression of a catalytically impaired isoform in myeloid cells. VEXAS syndrome combines severe auto-inflammatory manifestations and is frequently associated with myeloid neoplasia (MN). The outcome of VEXAS is poor, and most patients require high dose corticosteroids to reduce inflammation (Bourbon et al. Blood 2021). Therapeutic options besides steroids are currently limited in those patients. In this multicenter retrospective study, we report some clinical efficacy of JAK inhibitors (JAKi) in VEXAS patients. Patients We analyzed retrospectively 24 UBA1 mutated patients (Met41 or previously reported alternative splicing site) treated with JAKi (11 with ruxolitinib (RUXO), 11 with tofacitinib (TOFA), 1 with baricitinib, 1 with upadicitinib) in 7 French, 1 Portugese and 2 US centers. Complete clinical (CCR) and complete biological response (CBR) were defined as complete resolution of clinical symptoms and normalization of inflammation markers (C reactive protein, CRP) respectively. Partial clinical (PCR) and biological (PBR) response were defined by reduction of at least 50% of clinical or inflammation markers, respectively. Results All 24 patients were males with a median age at VEXAS diagnosis of 72 years [range 54-89]. Thirteen had documented myeloid neoplasia (MN) (1 CMML-0, 1 other MDS/MPN, 10 MDS). Clinical manifestations at VEXAS diagnosis include skin involvement (87.5%), arthritis or arthralgia (83.3%), vasculitis (37.5%), fever (75%), ocular manifestations (29.2%) and pulmonary infiltrates (41.6%). IPSS-R was very low/low/intermediate in 8/3/2 cases respectively. Median time between first VEXAS related clinical manifestations and JAKi onset was 2.45 years [0.15-5.45]. Prior to JAKi onset, patients had received a median of 2.5 immunosuppressive/immunomodulatory treatments [range 0-9]. After 1 month, 12/24 (50%) patients had achieved clinical and/or biological response. CCR and CBR was achieved in 7/11 (64%) and 6/11 (54%) patients treated with RUXO, and in 3/13 (23%) and 2/13 (15%) patients treated with other JAKi (figure A). After 3 months, CCR and CBR was 100% and 80% (10 evaluable patients) in the RUXO group as compared to 25% and 25 % in patients treated with other JAKi (8 evaluable patients) (p=0.0036 et 0.0055 respectively, figure B). RUXO efficacy was similar in patients with (n=9) or without (n=2) associated MN. In RUXO treated patients, median CRP and steroid dose reduction was 72.5% [range 21.5- 99.5] and 66.25% [range 0-75] respectively at 3 months. With a median follow-up of 4 months [range 1.4-12], only 1 RUXO treated patient had lost response, whereas median time to next of treatment was 3.4 months with other JAKi (figure C). Of the 13 patients with MN, 7 were RBC transfusion dependent at JAKi onset (6 with RUXO, 1 with other JAKi). Four of 6 patients treated with RUXO achieved RBC transfusion independence at 3 months, but not the patient treated with other JAKi. Regarding safety, severe adverse events were reported in 6 patients: 3 deep vein thrombosis, (2 with TOFA/1 with RUXO), 1 pneumonia (RUXO), 1 enterohemorrhagic E. Coli infection (RUXO), and 1 lethal legionellosis (TOFA)). Conclusion Ruxolitinib (and less often other JAK inhibitors used in this study) provides rapid response in most VEXAS patients, allowing in two third of the cases corticosteroid dose reduction/withdrawal and RBC transfusion independence in 4/6 patients with MN who were initially transfusion dependent. Those retrospective preliminary results, with limited follow up, must be interpreted with caution and will be updated at the meeting. The effect of RUXO on VEXAS patients with concomitant MN will soon be studied prospectively in a Groupe Francophone des Myélodysplasies (GFM) clinical study. Figure 1 Figure 1. Disclosures Galicier: Novartis Pharma Sas, Sanofi Aventis France: Consultancy; Lilly France, Baxalta France, Sanofi Aventis France Sas: Other: Payments as Speaker for Educational Program; Shire France SA, Janssen-Cilag, Pfizer Sas: Other: Invitation to Congress. Hirsch: Novartis Pharma: Consultancy; Daiichi Sankyo Oncology: Consultancy. Warrington: Eli Lilly: Research Funding; Kiniksa: Research Funding. Fenaux: Novartis: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene/BMS: Honoraria, Research Funding; Syros Pharmaceuticals: Honoraria.
- Published
- 2021
44. Somatic Mutations in a Single Residue of UBA1 Cause Vexas, a Severe Adult-Onset Rheumatic Disease Associated with Myeloid Dysplasia
- Author
-
Zhijie Wu, Shawn M. Burgess, Keith A. Sikora, Alina Dulau Florea, Emma M. Groarke, Daniel L. Kastner, Achim Werner, Neal S. Young, Peter C. Grayson, Bhavisha A Patel, Weixin Wang, David B. Beck, Katherine R. Calvo, Amanda K. Ombrello, Ivona Aksentijevich, and Marcela A. Ferrada
- Subjects
Myeloid ,business.industry ,Immunology ,Bone marrow failure ,Hematopoietic stem cell ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Haematopoiesis ,medicine.anatomical_structure ,medicine ,Bone marrow ,Stem cell ,business ,Exome - Abstract
Introduction: Identifying the causes of adult-onset rheumatic diseases remains a challenge, and limits diagnosis, prognosis, and targeted treatment. We hypothesized that mutations in genes regulating the post-translational modification ubiquitin, previously implicated in two autoinflammatory diseases, may define new rheumatic disorders. Methods: We analyzed peripheral blood exome sequence data from 2,560 individuals with inflammation-related diagnoses for deleterious mutations in >800 ubiquitin-related genes. After discovering three patients with novel UBA1 mutations, we identified additional cases based on clinical similarities through screening multiple independent cohorts. Clinical evaluation of all patients combined with Sanger sequencing, digital droplet PCR, immunoblotting, immunohistochemistry, flow cytometry, and transcriptome/cytokine profiling were performed. CRISPR/Cas9 edited zebrafish provided an in vivo model to assess UBA1 gene function. Results: Twenty-eight adult males were identified with somatic mutations at methionine 41 in UBA1, an X-linked gene, encoding the major E1 enzyme that initiates ubiquitylation. Methionine 41 is highly conserved in UBA1, and these mutations were not observed in exome sequences from over 80,000 healthy controls. Among affected individuals, mutations were found in more than half of hematopoietic stem cells, exclusively in peripheral blood myeloid cells, and not in lymphocytes or fibroblasts. The variant allele fraction of UBA1 p.Met41 mutations in peripheral blood ranged from 20-95%. Patients developed an often fatal, treatment-refractory inflammatory syndrome in late adulthood, with fever, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis and some individuals met clinical criteria for relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, or giant cell arteritis. In addition, the majority of subjects developed myelodysplastic bone marrow with cytopenias, characteristic vacuoles in myeloid and erythroid precursors cells, progressive bone marrow failure and thromboembolic disease, and some fulfilled clinical criteria for myelodysplastic syndrome or plasma cell dyscrasia. Transformation into MDS with excess blasts or acute myeloid leukemia did not occur in any case. Mutations at p.Met41, the initiation start site of the canonical cytoplasmic isoform, caused loss of this protein and expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral blood cells exhibited decreased ubiquitylation and activated innate immune pathways. Knockout of the zebrafish cytoplasmic UBA1 isoform homologue, but not the nuclear isoform, caused systemic inflammation. These results identify somatic mutations in UBA1 as the cause, and not the consequence, of this inflammatory disease. Conclusions: We have defined a novel disorder, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), which connects seemingly unrelated adult-onset inflammatory and hematologic diseases. Our work also reveals somatic mutations in a hematopoietic stem cell as a cause of adult-onset rheumatic syndromes that overlap with hematologic conditions. Identification of UBA1 mutations as a cause of these diseases has important implications for classification, prognosis, and treatment of patients, and for the role of somatic mutations of hematopoietic origin in multi-organ pathophysiology. Figure Disclosures Young: Novartis: Research Funding.
- Published
- 2020
45. Myelodysplasia and Bone Marrow Manifestations of Somatic UBA1 Mutated Autoinflammatory Disease
- Author
-
Daniel L. Kastner, Achim Werner, Megan Trick, Emma M. Groarke, David B. Beck, Zhijie Wu, Amanda K. Ombrello, Ifeyinwa Emmanuela Obiorah, Ivona Aksentijevich, Marcela A. Ferrada, Neal S. Young, Shawn M. Burgess, Keith A. Sikora, Peter C. Grayson, Weixin Wang, Katherine R. Calvo, Alina Dulau-Florea, and Bhavisha A Patel
- Subjects
Pathology ,medicine.medical_specialty ,Cytopenia ,Myeloid ,Lymphocytosis ,business.industry ,Immunology ,Cell Biology ,Hematology ,Plasma cell ,Neutropenia ,medicine.disease ,Biochemistry ,Germline mutation ,medicine.anatomical_structure ,hemic and lymphatic diseases ,medicine ,Monoclonal B-cell lymphocytosis ,Bone marrow ,medicine.symptom ,business - Abstract
Somatic mutations in UBA1 in hematopoietic stem cells and myeloid cells have recently been described and are associated with adult-onset severe autoinflammatory diseases including relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, and giant cell arteritis. This newly defined syndrome is named VEXAS (vacuoles, E1, X-linked, autoinflammatory, somatic). We performed clinicopathologic, cytogenetic, flow cytometric and molecular bone marrow assessment of 15 patients diagnosed with VEXAS and peripheral cytopenias. All patients were male, with a median age of 64y (IQR 45-80) and all had somatic missense mutations affecting the p.Met41 residue in UBA1 with variant allele frequencies (VAF) over 20% from peripheral blood or bone marrow samples and with lineage restriction to mature myeloid cells. Germline mutations at this residue are not reported in any public databases. Peripheral blood findings included macrocytic anemia in all patients (100%), thrombocytopenia in 9/15, and neutropenia in 1/15. All bone marrow aspirates (15/15; 100%) showed prominent vacuolization of both myeloid and erythroid precursors with few vacuoles noted in mature cells. Of the 9 patients tested for serum copper levels all were normal or borderline low. Marrow was hypercellular with granulocytic and megakaryocytic hyperplasia in 12/15 (80%). Definitive WHO criteria for MDS was met in 5/15 (40%) with 3 cases of MDS-MLD, and 2 of MDS-SLD. The remaining cases were suspicious for MDS with low or borderline levels of dyspoiesis that did not exceed greater than 10% of cells in respective lineages meeting criteria for clonal cytopenia of undetermined significance (CCUS). Of the MDS cases, dysplasia was seen in megakaryocytes (5/5), myeloid (2/5) and erythroid (1/5) precursors. Cytogenetic abnormalities were detected in 2/5 MDS patients involving t(3;12)(q21;q13) in one case, and del (5q)/del (13q) in another case. Next generation sequencing analyses were performed in 9/15 patients and showed mutations in DNMT3A in 2/5 MDS cases (VAF 43% and 44%), CSF1R in 1/5 MDS (VAF 3.1%), GNA11 in 1/5 MDS (VAF3.3%) and EZH2 mutation (VAF 22%) in one of the patients without overt MDS. Clonal plasma cell or B-cell populations were diagnosed in 6/15 patients with 3 plasma cell dyscrasias, and 2 cases of monoclonal B-cell lymphocytosis. The most common abnormalities detected by bone marrow flow cytometry analysis were severely reduced or absent B-cell precursors, inverted CD4:CD8 ratios and abnormal expression of CD56 on monocytes. In summary, hematologic disorders were identified in 10/15 VEXAS patients, including both myeloid and lymphoid clonal disease comprising MDS, plasma cell dyscrasias, and monoclonal B cell lymphocytosis. Based on the presence of UBA1 somatic mutations in hematopoietic cells of all VEXAS patients, the patients without evidence of overt neoplasia in this study met criteria for CCUS. Importantly, all patients had characteristic vacuoles in myeloid and erythroid precursors in the marrow without evidence of copper deficiency. These findings suggest that vacuolization of hematopoietic precursors in marrow of cytopenic patients, particularly in male patients and in the setting of systemic inflammation and normal copper levels, should prompt evaluation for somatic UBA1 mutations. In addition to severe autoinflammatory disease manifestations, VEXAS patients appear to confer increased risk for development of both myeloid and lymphoid/plasma cell neoplasia and require surveillance for disease progression. Figure Disclosures Young: Novartis: Research Funding.
- Published
- 2020
46. OP0090 CLASSIFICATION OF PATIENTS WITH RELAPSING POLYCHONDRITIS BASED ON SOMATIC MUTATIONS IN UBA1
- Author
-
P. Hoffman, Y. Lou, Anne Jones, Keith A. Sikora, DL Kastner, D. Ospina Cardona, Wendy Goodspeed, Amanda K. Ombrello, Bhavisha A Patel, Emily Rose, Lorena Wilson, Neal S. Young, David B. Beck, Kristina V. Wells, Marcela A. Ferrada, Sinisa Savic, and Peter C. Grayson
- Subjects
medicine.medical_specialty ,Tenosynovitis ,medicine.diagnostic_test ,business.industry ,Mortality rate ,Deep vein ,Immunology ,medicine.disease ,Gastroenterology ,General Biochemistry, Genetics and Molecular Biology ,medicine.anatomical_structure ,Rheumatology ,Internal medicine ,Cohort ,medicine ,Immunology and Allergy ,Chondritis ,business ,Exome ,Mean corpuscular volume ,Relapsing polychondritis - Abstract
Background:Somatic mutations in ubiquitin activating enzyme 1 (UBA1) cause a newly defined syndrome known as VEXAS. [1] More than fifty percent of patients currently identified with VEXAS meet diagnostic criteria for relapsing polychondritis (RP).Objectives:To determine the prevalence VEXAS within a cohort of patients with RP, to compare their clinical, laboratory, and immunologic features and to develop a clinical algorithm to inform genetic screening for VEXAS among patients with RP.Methods:Exome and targeted sequencing of the UBA1 gene was performed in a prospective observational cohort of patients with RP. Clinical and immunological characteristics of patients with RP were compared based on presence or absence of UBA1 mutations. Random forest was used to derive a clinical algorithm to identify patients with UBA1 mutations. Immune populations were quantified by multipanel flow cytometry. Categorical and continuous variables were compared using the chi square or Kruskal-Wallis test. PResults:Seven of 92 patients with RP (7.6%) were confirmed to have UBA1 mutations (VEXAS-RP). Six additional patients with VEXAS-RP from other cohorts were included for subsequent analyses. Patients with VEXAS-RP were all male, older at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. Patients with RP as compared with VEXAS-RP had a significantly higher prevalence of airway chondritis, costochondritis and tenosynovitis/arthralgias. (Table). Mortality was significantly greater in VEXAS-RP than RP (27% vs 2% p=0.01). Maximum ESR, CRP, and mean corpuscular volume (MCV) values were significantly greater in VEXAS-RP. Absolute monocyte, lymphocyte, and platelet counts were significantly lower in VEXAS-RP. A decision tree based on male sex, MCV>100 fl and Platelet countTable 1.Clinical Characteristics of patients with RP vs VEXAS-RPAll Patientsn=98RPn=85VEXAS-RPn=13p valueDemographic CharacteristicsRace, White n (%)90 (92)77 (91)13 (100)0.59Sex, Male n (%)26 (27)13 (15)13 (100)Age, Symptom onset, years, Median (IQR)38 (30-47)37 (28-43)56 (54-64)Clinical SymptomsFever n (%)33 (34)20 (24)13 (100)Ear chondritis n (%)61 (62)48 (56)13 (100)0.0015Nose chondritis n (%)83 (85)71 (84)12 (92)0.68Airway chondritis n (%)37 (38)37 (44)0 (0)0.0015Tenosynovitis/arthalgias n (%)83 (85)77 (91)6 (46)0.0005Skin involvement n (%)33 (34)22 (2611 (85)Laboratory ValuesESR, mm/hr, median (IQR)12 (6-22)11 (5-19)66.5 (42-110)CRP, mg/L, median (IQR)2.9 (0.8-9.6)1.9 (0.6-6.3)17.7 (9.6-99.5)Platelet count (k/uL)246(201-299)258 (227-312)145 (100-169)MCV fL93.05 (90-98)92.2 (89-95)105 (102-115)Absolute lymphocyte count1.6 (1.1-2.3)1.78(1.4-2.4)0.92 (0.5-1.2)CT scan abnormalitiesPulmonary infiltrates n (%)16 (16.33)6 (7.06)10 (77)ComplicationsDeath n (%)6 (6)3 (4)3 (23)0.029Unprovoked DVT12 (12)4 (5)8 (62)N number; IQR = interquartile rangeConclusion:Mutations in UBA1 are causal for disease in a subset of patients with RP. These patients are defined by disease onset in the fifth decade of life or later, male sex, ear/nose chondritis and hematologic abnormalities. Early identification is important in VEXAS given the associated high mortality rate.References:[1]Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z et al: Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020, 383(27):2628-2638.Disclosure of Interests:None declared
- Published
- 2021
47. Photoactivated In Vivo Proximity Labeling
- Author
-
David B. Beck and Roberto Bonasio
- Subjects
0301 basic medicine ,Streptavidin ,Light ,CHO Cells ,Biology ,Heterogeneous ribonucleoprotein particle ,Protein–protein interaction ,Jurkat Cells ,03 medical and health sciences ,chemistry.chemical_compound ,Cricetulus ,Biotin ,In vivo ,Cricetinae ,Animals ,Humans ,Biotinylation ,Cellular compartment ,Staining and Labeling ,030102 biochemistry & molecular biology ,Proteins ,DNA ,General Medicine ,Molecular biology ,HEK293 Cells ,030104 developmental biology ,chemistry ,Biophysics ,RNA ,Function (biology) - Abstract
Identification of molecular interactions is paramount to understanding how cells function. Most available technologies rely on co-purification of a protein of interest and its binding partners. Therefore, they are limited in their ability to detect low-affinity interactions and cannot be applied to proteins that localize to difficult-to-solubilize cellular compartments. In vivo proximity labeling (IPL) overcomes these obstacles by covalently tagging proteins and RNAs based on their proximity in vivo to a protein of interest. In IPL, a heterobifunctional probe comprising a photoactivatable moiety and biotin is recruited by a monomeric streptavidin tag fused to a protein of interest. Following UV irradiation, candidate interacting proteins and RNAs are covalently biotinylated with tight spatial and temporal control and subsequently recovered using biotin as an affinity handle. Here, we describe experimental protocols to discover novel protein-protein and protein-RNA interactions using IPL. © 2017 by John Wiley & Sons, Inc.
- Published
- 2017
48. Susceptibility to severe COVID-19
- Author
-
David B. Beck and Ivona Aksentijevich
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Pneumonia, Viral ,macromolecular substances ,Polymorphism, Single Nucleotide ,Betacoronavirus ,Polymorphism (computer science) ,Pandemic ,Humans ,Medicine ,Genetic Predisposition to Disease ,Pandemics ,Multidisciplinary ,biology ,SARS-CoV-2 ,business.industry ,COVID-19 ,biochemical phenomena, metabolism, and nutrition ,medicine.disease ,biology.organism_classification ,Virology ,Pneumonia ,Immune System Diseases ,Interferon Type I ,Coronavirus Infections ,business ,Interferon type I ,medicine.drug - Abstract
Genetic variants and autoantibodies that suppress antiviral immunity are linked to severe COVID-19
- Published
- 2020
49. Delineation of the First Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
- Author
-
Eleanor G. Seaby, Marwan Shinawi, Raymond J. Louie, Aida Telegrafi, Suzanne M. Leal, Julien Buratti, Ana Petracovici, David B. Beck, Muhammad Arif Nadeem Saqib, Boris Keren, Sivagamy Sithambaram, Muhammad Zahid, Marie-Christine Nougues, Sander Pajusalu, Jill A. Fahrner, Eloise J. Prijoles, G. Bradley Schaefer, Dustin Baldridge, Trudie Cottrell, Regie Lyn P. Santos-Cortez, Roberto Bonasio, Tiia Reimand, Muhammad Ansar, Kirsty McWalter, Sofia Douzgou, Cyril Mignot, Siddharth Banka, Hannah W. Moore, Chongsheng He, Roger E. Stevenson, Katrin Õunap, and Renee Bend
- Subjects
Genetics ,0303 health sciences ,biology ,Frameshift mutation ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Histone ,DNA demethylation ,DNA methylation ,biology.protein ,Mendelian inheritance ,symbols ,Epigenetics ,Global developmental delay ,Haploinsufficiency ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation of DNA (5mC) is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has been delineated. Here, we describe in detail the first Mendelian disorder caused by disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. Here we identify and characterize 11 cases of human TET3 deficiency in 8 families with the common phenotypic features of intellectual disability/global developmental delay, hypotonia, autistic traits, movement disorders, growth abnormalities, and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues with all but one occurring within the catalytic domain and most displaying hypomorphic function in a catalytic activity assay. TET3 deficiency shows substantial phenotypic overlap with other Mendelian disorders of the epigenetic machinery, including intellectual disability and growth abnormalities, underscoring shared disease mechanisms.
- Published
- 2019
- Full Text
- View/download PDF
50. Delineation of a Human Mendelian Disorder of the DNA Demethylation Machinery: TET3 Deficiency
- Author
-
Tiia Reimand, Kirsty McWalter, Eleanor G. Seaby, G. Bradley Schaefer, Marwan Shinawi, Muhammad Arif Nadeem Saqib, Aida Telegrafi, Ana Petracovici, Sander Pajusalu, Jill A. Fahrner, David B. Beck, Chongsheng He, Hannah W. Moore, Suzanne M. Leal, Raymond J. Louie, Siddharth Banka, Renee Bend, Regie Lyn P. Santos-Cortez, Roberto Bonasio, Boris Keren, Marie Christine Nougues, Eloise J. Prijoles, Muhammad Ansar, Katrin Õunap, Roger E. Stevenson, Julien Buratti, Sofia Douzgou, Cyril Mignot, Sivagamy Sithambaram, Trudie Cottrell, Dustin Baldridge, and Muhammad Zahid
- Subjects
0301 basic medicine ,Adult ,Male ,Protein Conformation ,Developmental Disabilities ,Embryonic Development ,Sequence Homology ,Frameshift mutation ,Dioxygenases ,03 medical and health sciences ,symbols.namesake ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Report ,Genetics ,Humans ,Epigenetics ,Amino Acid Sequence ,Autistic Disorder ,Child ,Genetics (clinical) ,Growth Disorders ,5-Hydroxymethylcytosine ,Movement Disorders ,biology ,Gene Expression Regulation, Developmental ,Infant ,Middle Aged ,Pedigree ,DNA Demethylation ,5-Methylcytosine ,030104 developmental biology ,Histone ,DNA demethylation ,chemistry ,Child, Preschool ,DNA methylation ,biology.protein ,Mendelian inheritance ,symbols ,Female ,030217 neurology & neurosurgery - Abstract
Germline pathogenic variants in chromatin-modifying enzymes are a common cause of pediatric developmental disorders. These enzymes catalyze reactions that regulate epigenetic inheritance via histone post-translational modifications and DNA methylation. Cytosine methylation (5-methylcytosine [5mC]) of DNA is the quintessential epigenetic mark, yet no human Mendelian disorder of DNA demethylation has yet been delineated. Here, we describe in detail a Mendelian disorder caused by the disruption of DNA demethylation. TET3 is a methylcytosine dioxygenase that initiates DNA demethylation during early zygote formation, embryogenesis, and neuronal differentiation and is intolerant to haploinsufficiency in mice and humans. We identify and characterize 11 cases of human TET3 deficiency in eight families with the common phenotypic features of intellectual disability and/or global developmental delay; hypotonia; autistic traits; movement disorders; growth abnormalities; and facial dysmorphism. Mono-allelic frameshift and nonsense variants in TET3 occur throughout the coding region. Mono-allelic and bi-allelic missense variants localize to conserved residues; all but one such variant occur within the catalytic domain, and most display hypomorphic function in an assay of catalytic activity. TET3 deficiency and other Mendelian disorders of the epigenetic machinery show substantial phenotypic overlap, including features of intellectual disability and abnormal growth, underscoring shared disease mechanisms.
- Published
- 2019
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.