TY - JOUR
T1 - Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis
AU - Ferrada, Marcela A.
AU - Savic, Sinisa
AU - Cardona, Daniela Ospina
AU - Collins, Jason C.
AU - Alessi, Hugh
AU - Gutierrez-Rodrigues, Fernanda
AU - Kumar, Dinesh Babu Uthaya
AU - Wilson, Lorena
AU - Goodspeed, Wendy
AU - Topilow, James S.
AU - Paik, Julie J.
AU - Poulter, James A.
AU - Kermani, Tanaz A.
AU - Koster, Matthew J.
AU - Warrington, Kenneth J.
AU - Cargo, Catherine
AU - Tattersall, Rachel S.
AU - Duncan, Christopher J.A.
AU - Cantor, Anna
AU - Hoffmann, Patrycja
AU - Payne, Elspeth M.
AU - Bonnekoh, Hanna
AU - Krause, Karoline
AU - Cowen, Edward W.
AU - Calvo, Katherine R.
AU - Patel, Bhavisha A.
AU - Ombrello, Amanda K.
AU - Kastner, Daniel L.
AU - Young, Neal S.
AU - Werner, Achim
AU - Grayson, Peter C.
AU - Beck, David B.
N1 - Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/9/29
Y1 - 2022/9/29
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2022016985
DO - 10.1182/blood.2022016985
M3 - Article
C2 - 35793467
AN - SCOPUS:85135690105
SN - 0006-4971
VL - 140
SP - 1496
EP - 1506
JO - Blood
JF - Blood
IS - 13
ER -