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Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease

Beck, David B; Ferrada, Marcela A; Sikora, Keith A; Ombrello, Amanda K; Collins, Jason C; Pei, Wuhong; Balanda, Nicholas; Ross, Daron L; Ospina Cardona, Daniela; Wu, Zhijie; Patel, Bhavisha; Manthiram, Kalpana; Groarke, Emma M; Gutierrez-Rodrigues, Fernanda; Hoffmann, Patrycja; Rosenzweig, Sofia; Nakabo, Shuichiro; Dillon, Laura W; Hourigan, Christopher S; Tsai, Wanxia L; Gupta, Sarthak; Carmona-Rivera, Carmelo; Asmar, Anthony J; Xu, Lisha; Oda, Hirotsugu; Goodspeed, Wendy; Barron, Karyl S; Nehrebecky, Michele; Jones, Anne; Laird, Ryan S; Deuitch, Natalie; Rowczenio, Dorota; Rominger, Emily; Wells, Kristina V; Lee, Chyi-Chia R; Wang, Weixin; Trick, Megan; Mullikin, James; Wigerblad, Gustaf; Brooks, Stephen; Dell'Orso, Stefania; Deng, Zuoming; Chae, Jae J; Dulau-Florea, Alina; Malicdan, May C V; Novacic, Danica; Colbert, Robert A; Kaplan, Mariana J; Gadina, Massimo; Savic, Sinisa; Lachmann, Helen J; Abu-Asab, Mones; Solomon, Benjamin D; Retterer, Kyle; Gahl, William A; Burgess, Shawn M; Aksentijevich, Ivona; Young, Neal S; Calvo, Katherine R; Werner, Achim; Kastner, Daniel L; Grayson, Peter C
BACKGROUND:Adult-onset inflammatory syndromes often manifest with overlapping clinical features. Variants in ubiquitin-related genes, previously implicated in autoinflammatory disease, may define new disorders. METHODS:We analyzed peripheral-blood exome sequence data independent of clinical phenotype and inheritance pattern to identify deleterious mutations in ubiquitin-related genes. Sanger sequencing, immunoblotting, immunohistochemical testing, flow cytometry, and transcriptome and cytokine profiling were performed. CRISPR-Cas9-edited zebrafish were used as an in vivo model to assess gene function. RESULTS:lies on the X chromosome.) In such patients, an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis. Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both. Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts. Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67. Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways. Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation. CONCLUSIONS:Using a genotype-driven approach, we identified a disorder that connects seemingly unrelated adult-onset inflammatory syndromes. We named this disorder the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. (Funded by the NIH Intramural Research Programs and the EU Horizon 2020 Research and Innovation Program.).
PMID: 33108101
ISSN: 1533-4406
CID: 5006912

Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis

Ferrada, Marcela A; Savic, Sinisa; Ospina Cardona, Daniela; Collins, Jason Charles; Alessi, Hugh; Gutierrez-Rodrigues, Fernanda; Uthaya Kumar, Dinesh Babu; Wilson, Lorena; Goodspeed, Wendy; Topilow, James S; Paik, Julie J; Poulter, James A; Kermani, Tanaz A; Koster, Matthew J; Warrington, Kenneth; Cargo, Catherine A; Tattersall, Rachel S; Duncan, Christopher Ja; Cantor, Anna; Hoffmann, Patrycja; Payne, Elspeth M; Bonnekoh, Hanna; Krause, Karoline; Cowen, Edward W; Calvo, Katherine R; Patel, Bhavisha A; Ombrello, Amanda K; Kastner, Daniel L; Young, Neal S; Werner, Achim; Grayson, Peter C; Beck, David B
Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predictors of survival in VEXAS and to understand the mechanistic basis for these factors. We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b). Patients with the p.Met41Val genotype were most likely to have an undifferentiated inflammatory syndrome. Multivariate analysis showed ear chondritis was associated with increased survival, while transfusion dependence and the p.Met41Val variant were independently associated with decreased survival. Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival. In addition, we show that these three canonical VEXAS variants produce more UBA1b than any of the six other possible single nucleotide variants within this codon. Finally, we report a patient, clinically diagnosed with VEXAS syndrome, with two novel mutations in UBA1 occurring in cis on the same allele. One mutation (c.121 A>T; p.Met41Leu) caused severely reduced translation of UBA1b in a reporter assay, but co-expression with the second mutation (c.119 G>C; p.Gly40Ala) rescued UBA1b levels to those of canonical mutations. We conclude that regulation of residual UBA1b translation is fundamental to the pathogenesis of VEXAS syndrome and contributes to disease prognosis.
PMID: 35793467
ISSN: 1528-0020
CID: 5268432

Disorders of ubiquitylation: unchained inflammation

Beck, David B; Werner, Achim; Kastner, Daniel L; Aksentijevich, Ivona
Ubiquitylation is an essential post-translational modification that regulates intracellular signalling networks by triggering proteasomal substrate degradation, changing the activity of substrates or mediating changes in proteins that interact with substrates. Hundreds of enzymes participate in reversible ubiquitylation of proteins, some acting globally and others targeting specific proteins. Ubiquitylation is essential for innate immune responses, as it facilitates rapid regulation of inflammatory pathways, thereby ensuring sufficient but not excessive responses. A growing number of inborn errors of immunity are attributed to dysregulated ubiquitylation. These genetic disorders exhibit broad clinical manifestations, ranging from susceptibility to infection to autoinflammatory and/or autoimmune features, lymphoproliferation and propensity to malignancy. Many autoinflammatory disorders result from disruption of components of the ubiquitylation machinery and lead to overactivation of innate immune cells. An understanding of the disorders of ubiquitylation in autoinflammatory diseases could enable the development of novel management strategies.
PMCID:9075716
PMID: 35523963
ISSN: 1759-4804
CID: 5216652

The common HAQ STING allele prevents clinical penetrance of COPA syndrome

Simchoni, Noa; Koide, Shogo; Likhite, Maryel; Kuchitsu, Yoshihiko; Kadirvel, Senkottuvelan; Law, Christopher S; Elicker, Brett M; Kurra, Santosh; Wong, Margaret Mei-Kay; Yuan, Bo; Grossi, Alice; Laxer, Ronald M; Volpi, Stefano; Dissanayake, Dilan; Taguchi, Tomohiko; Beck, David B; Vogel, Tiphanie P; Shum, Anthony K
COPA syndrome, an autosomal-dominant inborn error of immunity, is nonpenetrant in ∼20% of individuals, with no known mediators of protection. Recent studies implicate STING in the pathogenesis of COPA syndrome. We show that the common HAQ STING allele mediates complete clinical protection. We sequenced 35 individuals with COPA mutations, 26 affected patients and 9 unaffected carriers, finding HAQ STING co-segregation with clinical nonpenetrance. Exome sequencing identified only the mutations comprising HAQ STING as variants shared by unaffected carriers and absent in patients. Experimentally, we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling. Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome. Our study is the first report of a common and well-tolerated allele mediating complete clinical protection from a severe genetic disorder. Our findings redefine the diagnostic criteria for COPA syndrome, expose functional differences among STING alleles with broad scientific and clinical implications, and reveal a potential universal gene therapy approach for patients.
PMCID:11867111
PMID: 40014299
ISSN: 1540-9538
CID: 5801232

The Present and Future of Genetic Sequencing as Applied to Diagnosis and Management in Rheumatology

Liebowitz, Jason; Rasouly, Hila Milo; Bogyo, Kelsie; Petukhova, Lynn; Bernstein, Elana J; Schwartz, Daniella M; Grayson, Peter C; Beck, David; Luo, Yiming
PMID: 40181789
ISSN: 2326-5205
CID: 5819362

Germline UBA1 Variant With Somatic Amplification in a Woman With Inflammatory Diseases and Myelodysplastic Syndrome

Creignou, Maria; Sirenko, Maria; Moura, Pedro L; Mortera-Blanco, Teresa; Dimitriou, Marios; Sander, Birgitta; Domenico, Dylan; Arango Ossa, Juan E; Tesi, Bianca; Beck, David B; Woll, Petter; Jacobsen, Sten-Eirik W; Papaemmanuil, Elli; Bernard, Elsa; Hellström-Lindberg, Eva
PMID: 39832370
ISSN: 1539-3704
CID: 5802102

Improving Outcomes in VEXAS Syndrome: The Need for Prospective Data

Hadjadj, Jerome; Beck, David B
PMID: 39862397
ISSN: 1462-0332
CID: 5802732

Somatic mutations in autoinflammatory and autoimmune disease

Torreggiani, Sofia; Castellan, Flore S; Aksentijevich, Ivona; Beck, David B
Somatic mutations (also known as acquired mutations) are emerging as common, age-related processes that occur in all cells throughout the body. Somatic mutations are canonically linked to malignant processes but over the past decade have been increasingly causally connected to benign diseases including rheumatic conditions. Here we outline the contribution of somatic mutations to complex and monogenic immunological diseases with a detailed review of unique aspects associated with such causes. Somatic mutations can cause early- or late-onset rheumatic monogenic diseases but also contribute to the pathogenesis of complex inflammatory and immune-mediated diseases, affect disease progression and define new clinical subtypes. Although even variants with a low variant allele fraction can be pathogenic, clonal dynamics could lead to changes over time in the proportion of mutant cells, with possible phenotypic consequences for the individual. Thus, somatic mutagenesis and clonal expansion have relevant implications in genetic testing and counselling. On the basis of both increased recognition of somatic diseases in clinical practice and improved technical and bioinformatic processes, we hypothesize that there will be an ever-expanding list of somatic mutations in various genes leading to inflammatory conditions, particularly in late-onset disease.
PMID: 39394526
ISSN: 1759-4804
CID: 5730252

Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis

Bisikirska, Brygida; Labella, Rossella; Cuesta-Dominguez, Alvaro; Luo, Na; De Angelis, Jessica; Mosialou, Ioanna; Lin, Chyuan-Sheng; Beck, David; Lata, Sneh; Shyu, Peter Timothy; McMahon, Donald J; Guo, Edward; Hagen, Jacob; Chung, Wendy K; Shane, Elizabeth; Cohen, Adi; Kousteni, Stavroula
Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (MTNR1A) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [MTNR1Ac.184+1G>T (MTNR1A
PMID: 39413162
ISSN: 1946-6242
CID: 5711652

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

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