[Nakajo-Nishimura syndrome].

Area of Science:

• Genetics
• Immunology
• Molecular Biology

Context:

• Nakajo-Nishimura syndrome (NNS) is a rare inherited autoinflammatory disease.
• Characterized by inflammatory symptoms, wasting, and specific physical manifestations starting in infancy.
• Previously, the genetic cause of NNS remained undefined.

Purpose:

• To identify the genetic basis of Nakajo-Nishimura syndrome.
• To elucidate the molecular mechanisms underlying NNS pathogenesis.
• To establish NNS as a proteasome deficiency syndrome.

Summary:

• Identified homozygous mutations in the PSMB8 gene, encoding the immunoproteasome β5i subunit, as the cause of NNS.
• Demonstrated that deficiency in proteasome activity leads to the accumulation of ubiquitinated and oxidized proteins.
• Linked proteasome dysfunction to the hyperactivation of p38 MAPK and overproduction of IL-6, driving the autoinflammatory phenotype.

Impact:

• Establishes proteasome dysfunction as a novel mechanism in autoinflammatory diseases.
• Highlights the global distribution of PSMB8-related proteasome deficiency syndromes.
• Provides a molecular basis for understanding and potentially treating NNS and similar disorders.