Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.

Proteasome Disability Syndrome: An Analysis of the Pathogenesis of a New Autoinflammatory Syndrome, Nakajo-Nishimura Syndrome.

Ida1,  Hiroaki, Arima2,  Kazuhiko, Kanazawa3,  Nobuo, Yoshiura2,  Koh-ichiro

Kurume University School of Medicine, Kurume, Japan
Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
Wakayama Medical University, Wakayama, Japan


Nakajo-Nishimura syndrome (NNS) (MIM 256040) is a new autoinflammatory disorder that segregates in an autosomal recessive fashion and shows inflammatory and wasting symptoms including periodic fever, skin rash, myositis, partial lipodystrophy, contracture of joints and calcification of basal ganglia. The purpose of this study is to detect the responsible gene and to analyze the molecular features in cells from patients with NNS.


1) Genomic DNA samples were analyzed with the SNP microarray-based homozygosity mapping following to determine the affected gene by direct sequencing. 2) Proteins from immortalized NNS lymphoblastoid cell lines were separated into fractions by glycerol gradient. Each fraction was assayed for 3 different peptidase activities of the proteasome, chymotrypsin-like, trypsin-like, and caspase-like activities, using the fluorescent peptide substrates. 3) An amount of proteasome subunits and accumulation of ubiquitinated proteins were detected by Western blotting. 4) Immunological staining was performed on skin biopsy sections obtained from NNS patients. 5) Concentrations of 27 different cytokines were determined using a multiplex bead-based enzyme linked immunosorbent assay on a suspension array in serum samples obtained from healthy controls (HC), rheumatoid arthritis (RA) patients, and NNS patients. 6) We investigated activation of the various signal transduction pathways that could be responsible for inflammation using EMSA and Western blotting.


1) We detected a homozygous mutation in the human PSMB8 gene that encodes immunoproteasome subunit b5i in patients with NNS. 2) The resultant amino acid substitution (G201V) abolished all three peptidase activities of proteasome and 3) disturbed maturation of the immunoproteasome complex. 4) Accumulation of ubiquitinated proteins was detected in the NNS lymphoblasts and infiltrating cells in the skin lesion of patients with NNS. 5) The productions of inflammatory cytokine (IL-6) and chemokine (IP-10) were seen in greater numbers in sera from NNS patients compared to HC and RA. 6) While no differences in the amount of the NF-kB p65/p50 heterodimer were observed in nuclear extracts from NNS and HC fibroblasts, the amounts of phosphorylated p38 (p-p38) in the nuclear extracts from NNS fibroblasts and peripheral blood leukocytes were seen in larger amounts, irrespective of TNF-a stimulation.


Our findings reveal that a decrease in proteasome activity, which is associated with a novel mutation of the b5i immunoproteasome subunit, causes definitive human autoinflammatory phenotypes in NNS. This fact suggests that the ubiquitin-proteasome pathway might play an important role for inflammation and provides a new insight into the pathogenesis of other persistent inflammatory diseases.

To cite this abstract, please use the following information:
Ida, Hiroaki, Arima, Kazuhiko, Kanazawa, Nobuo, Yoshiura, Koh-ichiro; Proteasome Disability Syndrome: An Analysis of the Pathogenesis of a New Autoinflammatory Syndrome, Nakajo-Nishimura Syndrome. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2447

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