PSMC3 encodes a subunit of 19S regulatory particle from proteasome 26S. Its variants lead to proteostatic imbalances, characterized by an accumulation of polyubiquitinated proteins in the cell due to proteasomal dysfunction. The variants also cause proteotoxic stress and alterations in proteins controlling developmental and innate immune programs. All blood samples measured were in particular characterized by a type I interferon signature typical for interferonopathies according to the method of Rice et al., (2017) (PMID: 27943079). Samples are considered as abnormal with an interferon score above >2.466 using the median expression of six interferon stimulated genes (IFI27; IFIT1, IFI44L, ISG15; RSAD2, SIGLEC1) normalized to HPRT and 18S by qPCR. The interferon score can be recapitulated in T cells expanded from blood samples of patients irrespective of medication.
Thus far, all identified genetic variants altering PSMC3 function are de novo. These are mainly missense variations that affect the ATPase domain, causing a loss of proteasomal function. However, a few frameshift variants have been found too, which also induce a loss of function, most likely through haploinsufficiency.
PSMC3