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Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis
  1. Naomi Tsuchida1,2,
  2. Yosuke Kunishita1,
  3. Yuri Uchiyama2,3,
  4. Yohei Kirino1,
  5. Makiko Enaka4,
  6. Yukie Yamaguchi5,
  7. Masataka Taguri6,
  8. Shoji Yamanaka7,
  9. Kaoru Takase-Minegishi1,
  10. Ryusuke Yoshimi1,
  11. Satoshi Fujii4,7,
  12. Hideaki Nakajima1,
  13. Naomichi Matsumoto2
  1. 1Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  2. 2Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  3. 3Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan
  4. 4Department of Molecular Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  5. 5Department of Environmental Immuno-Dermatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  6. 6Department of Data Science, School of Data Science, Yokohama City University, Yokohama, Japan
  7. 7Department of Pathology, Yokohama City University Hospital, Yokohama, Japan
  1. Correspondence to Dr Yohei Kirino, Department of Stem Cell and Immune Regulation, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan; kirino{at}yokohama-cu.ac.jp

Abstract

Objectives To determine clinical and genetic features of individuals with relapsing polychondritis (RP) likely caused by pathogenic somatic variants in ubiquitin-like modifier activating enzyme 1 (UBA1).

Methods Fourteen patients with RP who met the Damiani and Levine criteria were recruited (12 men, 2 women; median onset age (IQR) 72.1 years (67.1–78.0)). Sanger sequencing of UBA1 was performed using genomic DNA from peripheral blood leukocytes or bone marrow tissue. Droplet digital PCR (ddPCR) and peptide nucleic acid (PNA)-clamping PCR were used to detect low-prevalence somatic variants. Clinical features of the patients were investigated retrospectively.

Results UBA1 was examined in 13 of the 14 patients; 73% (8/11) of the male patients had somatic UBA1 variants (c.121A>C, c.121A>G or c.122T>C resulting in p.Met41Leu, p.Met41Val or p.Met41Thr, respectively). All the variant-positive patients had systemic symptoms, including a significantly high prevalence of skin lesions. ddPCR detected low prevalence (0.14%) of somatic variant (c.121A>C) in one female patient, which was subsequently confirmed by PNA-clamping PCR.

Conclusions Genetic screening for pathogenic UBA1 variants should be considered in patients with RP, especially male patients with skin lesions. The somatic variant in UBA1 in the female patient is the first to be reported.

  • immune system diseases
  • systemic vasculitis
  • polymorphism
  • genetic

Data availability statement

Data are available upon reasonable request. The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Data availability statement

Data are available upon reasonable request. The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Footnotes

  • Handling editor Josef S Smolen

  • NT and YKcontributed equally.

  • Contributors Conception and design: YohK. Analysis and interpretation of the data: NT, YosK, YohK, YU, ME, YY, MT and NM. Critical revision for important intellectual content and final approval of the article: all authors. Obtaining of funding: NT, YosK, YU, YohK, RY, HN and NM. Collection and assembly: NT, YosK, YohK and NM.

  • Funding This study was supported by grants from the Japanese Society for the Promotion of Science Grants-in-Aid for Scientific Research JP19H03700 (to YohK), JP20K17428 (to NT), JP19K23847 and JP20K17446 (to YosK), JP19K08914 (to RY), JP20H03714 (to HN), JP19K17865 (to YU) and JP17H01539 (to NM); AMED under grant numbers JP20ek0109486, JP20dm0107090, JP20ek0109301, JP20ek0109348 and JP20kk0205012 (to NM); intramural grants (30-6 and 30-7) of NCNP from the Ministry of Health, Labour and Welfare (to NM) and the Takeda Science Foundation (to NM).

  • Competing interests YohK reports personal fees from Amgen, grants from Chugai and grants from Ono, outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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