Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation

Arthritis Rheumatol. 2022 Jun;74(6):1083-1090. doi: 10.1002/art.42070. Epub 2022 Apr 23.


Objective: Proteasome-associated autoinflammatory syndrome (PRAAS) is caused by mutations affecting components of the proteasome and activation of the type I interferon (IFN) pathway. This study was undertaken to investigate the pathogenic mechanisms of a newly recognized type of PRAAS caused by PSMD12 haploinsufficiency.

Methods: Whole-exome sequencing was performed in members of a family with skin rash, congenital uveitis, and developmental delay. We performed functional studies to assess proteasome dysfunction and inflammatory signatures in patients, and single-cell RNA sequencing to further explore the spectrum of immune cell activation.

Results: A novel truncated variant in PSMD12 (c.865C>T, p.Arg289*) was identified in 2 family members. The impairment of proteasome function was found in peripheral blood mononuclear cells (PBMCs), as well as in PSMD12-knockdown HEK 293T cell lines. Moreover, we defined the inflammatory signatures in patient PBMCs and found elevated IFN signals, especially in monocytes, by single-cell RNA sequencing.

Conclusion: These findings indicate that PSMD12 haploinsufficiency causes a set of inflammation signatures in addition to neurodevelopmental disorders. Our work expands the genotype and phenotype spectrum of PRAAS and suggests a bridge between the almost exclusively inflammatory phenotypes in the majority of PRAAS patients and the almost exclusively neurodevelopmental phenotypes in the previously reported Stankiewicz-Isidor syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Exome Sequencing
  • Haploinsufficiency* / genetics
  • Humans
  • Leukocytes, Mononuclear / metabolism
  • Phenotype
  • Proteasome Endopeptidase Complex* / genetics
  • Proteasome Endopeptidase Complex* / metabolism
  • Syndrome


  • Proteasome Endopeptidase Complex