Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Haploinsufficiency of PSMD12 causes proteasome dysfunction and subclinical autoinflammation.

Abstract

OBJECTIVE: Proteasome-associated autoinflammatory syndrome (PRAAS) is caused by mutations affecting components of the proteasome and activation of the type I interferon pathway. The purpose of this study was to investigate the pathogenic mechanisms of a new type of PRAAS caused by PSMD12 haploinsufficiency. METHODS: Whole exome sequencing (WES) was analyzed in 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 (scRNA-seq) to further explore the spectrum of immune cell activation. RESULTS: A novel truncated variant in PSMD12 (c.865C>T, p.Arg289*) in two patients was identified. The impairment of proteasome function was found in patients PBMCs, as well as in PSMD12 knock-down HEK293T cell lines. Moreover, we defined the inflammatory signatures in patient PBMCs and found elevated IFN signals especially in monocytes by scRNA-seq. CONCLUSION: PSMD12 haploinsufficiency causes a set of inflammation signatures besides neurodevelopmental disorders. Our work expands the genotype and phenotype spectrums of PRAAS, and makes a bridge between the almost exclusively inflammatory phenotypes in the majority of PRAAS patients to the almost exclusively neurodevelopmental phenotypea in previously reported Stankiewicz-Isidor syndrome (STISS) (OMIM: 604450).