Drs. Liu and Ramot contributed equally to this work.
Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity
Article first published online: 28 FEB 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 3, pages 895–907, March 2012
How to Cite
Liu, Y., Ramot, Y., Torrelo, A., Paller, A. S., Si, N., Babay, S., Kim, P. W., Sheikh, A., Lee, C.-C. R., Chen, Y., Vera, A., Zhang, X., Goldbach-Mansky, R. and Zlotogorski, A. (2012), Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis & Rheumatism, 64: 895–907. doi: 10.1002/art.33368
- Issue published online: 28 FEB 2012
- Article first published online: 28 FEB 2012
- Accepted manuscript online: 27 SEP 2011 10:22AM EST
- Manuscript Accepted: 20 SEP 2011
- Manuscript Received: 9 JUN 2011
- Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH
- Authority for Research and Development, Hebrew University of Jerusalem
- Hadassah Medical Center Young Clinician Award
Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE syndrome) is an autoinflammatory syndrome recently described in children. We undertook this study to investigate the clinical phenotype, genetic cause, and immune dysregulation in 9 CANDLE syndrome patients.
Genomic DNA from all patients was screened for mutations in PSMB8 (proteasome subunit β type 8). Cytokine levels were measured in sera from 3 patients. Skin biopsy samples were evaluated by immunohistochemistry, and blood microarray profile and STAT-1 phosphorylation were assessed in 4 patients and 3 patients, respectively.
One patient was homozygous for a novel nonsense mutation in PSMB8 (c.405C>A), suggesting a protein truncation; 4 patients were homozygous and 2 were heterozygous for a previously reported missense mutation (c.224C>T); and 1 patient showed no mutation. None of these sequence changes was observed in chromosomes from 750 healthy controls. Of the 4 patients with the same mutation, only 2 shared the same haplotype, indicating a mutational hot spot. PSMB8 mutation–positive and –negative patients expressed high levels of interferon-γ (IFNγ)–inducible protein 10. Levels of monocyte chemotactic protein 1, interleukin-6 (IL-6), and IL-1 receptor antagonist were moderately elevated. Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders.
CANDLE syndrome is caused by mutations in PSMB8, a gene recently reported to cause “JMP” syndrome (joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced childhood-onset lipodystrophy) in adults. We extend the clinical and pathogenic description of this novel autoinflammatory syndrome, thereby expanding the clinical and genetic disease spectrum of PSMB8-associated disorders. IFN may be a key mediator of the inflammatory response and may present a therapeutic target.