The homozygous founder Psmb8 variant of Nakajo-Nishimura syndrome/proteasome-associated autoinflammatory syndrome causes panniculitis-associated lipoatrophy and a shortened lifespan in mice

Clinically, NNS/PRAAS is characterized by periodic fever, skin rash, partial lipo-muscular atrophy, and joint contractures. Among PRAAS, NNS, is genetically characterized by a homozygous founder variant in the proteasome subunit beta type 8 (PSMB8) gene encoding an inducible proteasome component β5i.

To establish an in vivo animal model recapitulating NNS/PRAAS , we generated mice harboring this founder variant. In Psmb8G201V/G201V mice, the immature β5i subunit was increased and 20S proteasome activity was significantly reduced in the spleen, whereas 26S proteasome activity was preserved and ubiquitin accumulation was not apparent. Compared with wild-type mice, Psmb8G201V/G201V mice exhibited a shortened lifespan and, as they aged, showed less weight gain and adipocyte shrinkage with interstitial macrophage infiltration and cytokine production/activation.