Additive loss of function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
Autosomal recessive mutations in proteasome subunit b 8 (PSMB8) which encodes the inducible proteasome subunit b5i, cause the immune dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) which is classified as a proteasome associated autoinflammatory syndrome (PRAAS) Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes a7) PSMB4 (encodes b7) PSMB9 (encodes b1i) and proteasome maturation protein (POMP) that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene expression signature, irrespective of genotype. Additionally, chemical Research Article Immunology
The Journal of clinical investigation