title: Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH, Bethesda, MD 20892, USA.
authors.forename: Yin
authors.initials: Y
authors.lastname: Liu
authors.forename: Yuval
authors.initials: Y
authors.lastname: Ramot
authors.forename: Antonio
authors.initials: A
authors.lastname: Torrelo
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Nuo
authors.initials: N
authors.lastname: Si
authors.forename: Sofia
authors.initials: S
authors.lastname: Babay
authors.forename: Peter W
authors.initials: PW
authors.lastname: Kim
authors.forename: Afzal
authors.initials: A
authors.lastname: Sheikh
authors.forename: Chyi-Chia Richard
authors.initials: CC
authors.lastname: Lee
authors.forename: Yongqing
authors.initials: Y
authors.lastname: Chen
authors.forename: Angel
authors.initials: A
authors.lastname: Vera
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Raphaela
authors.initials: R
authors.lastname: Goldbach-Mansky
authors.forename: Abraham
authors.initials: A
authors.lastname: Zlotogorski
mesh_terms: D000293:Adolescent; D054357:Chemokine CXCL10 / Q000097:blood; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D005838:Genotype; D006801:Humans; D007371:Interferon-gamma / Q000097:blood; D008060:Lipodystrophy / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D046988:Proteasome Endopeptidase Complex / Q000097:blood / Q000235:genetics*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D016463:Sweet Syndrome / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D013577:Syndrome
chemical_list: D054357:Chemokine CXCL10; D018389:Codon, Nonsense; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D007371:Interferon-gamma; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex