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<p>VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe inflammatory and hematologic disease caused by somatic mutations in <i>UBA1</i>. Canonical pathogenic mutations at <i>UBA1</i> p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms. Studies have reported clinical differences between canonical and non-canonical mutations, but these findings are constrained by small sample sizes and scarcity of genetic studies. In our study, we screened 29,000 individuals for <i>UBA1</i> variants, referred for a broad range of hematologic diseases, and subjected to 62-gene panel sequencing, identifying 232 patients carrying likely disease-causing mutations. We identified decreased polyubiquitylation in all of the 18 <i>UBA1</i> variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations. Our findings confirm that patients harboring M41 mutations present at most with myelodysplastic neoplasms (MDS) and suggest that M41 mutations generally do not tolerate multiple co-mutations. In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS. Our study establishes that M41 and non-M41 mutations exhibit distinct clinical and biological phenotypes, significantly enhancing <i>UBA1</i> variant interpretation.</p>

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Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月9日

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  • Maki Sakuma,
  • Amy K. Wang,
  • Samuel J. Magaziner,
  • Sachiko P. Keane,
  • Manja Meggendorfer,
  • Wolfgang Kern,
  • Claudia Haferlach,
  • Torsten Haferlach,
  • David B. Beck,
  • Wencke Walter

摘要

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a severe inflammatory and hematologic disease caused by somatic mutations in UBA1. Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms. Studies have reported clinical differences between canonical and non-canonical mutations, but these findings are constrained by small sample sizes and scarcity of genetic studies. In our study, we screened 29,000 individuals for UBA1 variants, referred for a broad range of hematologic diseases, and subjected to 62-gene panel sequencing, identifying 232 patients carrying likely disease-causing mutations. We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations. Our findings confirm that patients harboring M41 mutations present at most with myelodysplastic neoplasms (MDS) and suggest that M41 mutations generally do not tolerate multiple co-mutations. In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS. Our study establishes that M41 and non-M41 mutations exhibit distinct clinical and biological phenotypes, significantly enhancing UBA1 variant interpretation.