Pathophysiology of hereditary intractable disease "Nakajo-Nishimura syndrome" replicated

A research group including Assistant Professor Tomoyuki Hara of the School of Medicine at Wakayama Medical University, Professor Nobuo Kanazawa, Head of the Department of Dermatology at Hyogo Medical University, and Lecturer Akira Kinoshita of the Atomic Bomb Disease Institute at Nagasaki University, in collaboration with the University of Tokyo, has successfully established a novel model mouse for Nakajo-Nishimura syndrome (NNS), a hereditary intractable disease. They confirmed that the mouse possesses the genetic mutation found in all patients with the disease and replicates its pathophysiology with high precision. This achievement is expected to contribute to the development of new therapies and the elucidation of the disease's underlying mechanisms. The results were published in Scientific Reports on May 28.

NNS is a hereditary intractable disease characterized by symptoms such as periodic fever, chilblain-like erythema, and progressive lipomuscular atrophy, with many cases resulting in early death. To date, approximately 30 cases have been reported in Japan, and reports have now emerged from outside the country as well. It is known to be caused by a decrease in proteasome function due to homozygous or compound heterozygous mutations in the PSMB8 gene, which encodes the β5i subunit of the proteasome. While steroids and JAK inhibitors are effective for some symptoms, they have no effect on partial lipomuscular atrophy, and no curative treatment currently exists.

Previously, in 2018, the research group collaborated with the Center for iPS Cell Research and Application (CiRA) at Kyoto University to generate ES cells and iPS cells introducing this specific genetic mutation, which clarified the inflammatory mechanisms and other aspects of the disease.

Building on that work, the research group sought to analyze the pathophysiology by creating a model mouse for the disease. First, using homologous recombination in mouse ES cells, they generated mice carrying the p.Gly201Val genetic mutation common to all patients with the disease. They successfully created a model mouse (Psmb8^G201V/G201V) possessing a homozygous state for this genetic mutation.

Half of these model mice died within one year. While there was no weight difference in the early stages of life, the model mice exhibited significant poor weight gain between 30 and 65 weeks of age compared to wild-type mice. At 89 weeks of age, atrophy of both subcutaneous and visceral adipocytes (fat cells) was confirmed, accompanied by the infiltration of inflammatory cells in the surrounding areas.

Furthermore, at 16 to 20 weeks of age, the proportion of CD8⁺T cells in the spleen was significantly reduced. Specifically, naive T cells decreased while central memory T cells increased. This suggests that immune aging may be occurring.

Cytokine analysis revealed that serum IL-6 was significantly elevated in model mice over 46 weeks of age, and a significant elevation of IL-1α was observed in model mice over 60 weeks of age.

Conversely, the model mice did not exhibit the accumulation of ubiquitinated proteins, chilblain-like symptoms, or elevations in serum IP-10 and MCP-1 seen in human patients, nor was there an enhancement of Type I TFN activation. The researchers thus confirmed that the phenotype partially differs from that of human patients.

The established mouse model is expected to serve as an important tool not only for elucidating the pathophysiology of NNS but also for evaluating the efficacy and safety of novel therapeutic agents.

Hara stated: "Moving forward, we first want to investigate whether JAK inhibitors, which have proven effective in humans, show efficacy in our model mice. We also plan to examine whether the characteristics confirmed in the mice are observable in human patients, thereby connecting this research to the development of new treatments."

Kanazawa noted: "Next, we hope to verify the effects of HDAC inhibitors, whose efficacy has already been confirmed through iPS cell screening at this point. By advancing these studies, we aim to discover medications that can be directly channeled back to benefit patients."

Journal Information
Publication: Scientific Reports
Title: The homozygous founder Psmb8 variant of Nakajo-Nishimura syndrome/proteasome-associated autoinflammatory syndrome causes panniculitis-associated lipoatrophy and a shortened lifespan in mice
DOI: 10.1038/s41598-026-51190-x