Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation

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.