Monoallelic PSMB8 variants cause PRAAS with immunodeficiency through impaired immunoproteasome assembly.

Monoallelic PSMB8 variants → dominant-negative mechanism → impaired immunoproteasome assembly → integrated stress response activation → immunodeficiency and systemic inflammation

Seven individuals from five unrelated families with five distinct monoallelic PSMB8 variants present with PRAAS-ID: neonatal immunodeficiency with recurrent infections, B cell lymphopenia, hypogammaglobulinemia, and variable inflammatory manifestations (enteropathy, hepatitis, myositis). Complexome profiling on fibroblasts reveals that pathogenic variants impair immunoproteasome assembly via a dominant-negative mechanism. Conserved structural positions shared by PSMB9 and PSMB10 may help identify future pathogenic variants.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

This study clarifies that monoallelic PSMB8 variants cause PRAAS-ID — a distinct phenotype from the more severe biallelic form. The demonstration of a unified dominant-negative mechanism for immunoproteasome catalytic subunits (PSMB8/9/10) is a major mechanistic contribution that will facilitate variant interpretation in molecular diagnosis.

Clinical impact: 1/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 1/1 · Journal quality: 1/1 → Total: 7/10