PSMB8 – Proteasome-associated autoinflammatory syndrome

Biallelic variants in the immunoproteasome subunit gene PSMB8 underlie autosomal recessive proteasome-associated autoinflammatory syndrome (Proteasome-associated autoinflammatory syndrome), manifesting in early infancy with recurrent fever, skin lesions, and progressive lipodystrophy. The condition spans Nakajo-Nishimura syndrome (NNS) and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE).

Genetic evidence includes at least 18 unrelated probands with homozygous or compound heterozygous PSMB8 variants identified across Japanese, European, Chinese, Brazilian, Algerian, and Bulgarian cohorts (PMID:23942189; PMID:25036278; PMID:26567544; PMID:31046790; PMID:32513120; PMID:37654638; PMID:32144790; PMID:21953331). Segregation analyses in consanguineous families demonstrate cosegregation of homozygous variants with disease in multiple affected siblings (PMID:26567544; PMID:22441638). Recurrent hotspot variants, notably c.224C>T (p.Thr75Met) and c.405C>A (p.Cys135Ter), have been observed in distinct populations.

Clinical presentations converge on early-onset periodic fever (HP:0001954), erythematous skin rash (HP:0000988), progressive partial lipodystrophy (HP:0009125), and hepatosplenomegaly (HP:0001433). Additional features include generalized lymphadenopathy, basal ganglia calcification, clubbing of fingers, and autoimmune cytopenias.

Functional studies reveal that the p.Gly201Val immunoproteasome variant impairs β5i incorporation, reducing proteasome activity, leading to ubiquitinated protein accumulation, heightened IL-6 expression, and defective adipocyte differentiation in vitro and in vivo (PMID:21881205). In CANDLE patients, PSMB8 missense and nonsense alleles trigger a robust type I interferon signature, elevated IFNγ-inducible chemokines, and STAT-1 hyperphosphorylation (PMID:21953331). siRNA knockdown of proteasome subunits in primary fibroblasts recapitulates inflammatory signaling, and baricitinib treatment ameliorates clinical symptoms and growth delay (PMID:26524591; PMID:31046790).

No conflicting genetic or phenotypic evidence has been reported; all studies consistently link PSMB8 deficiency to PRAAS. The weight of genetic, segregation, and functional data supports a Definitive gene-disease association.

Key Take-home: Molecular testing for PSMB8 variants should be performed in infants with early-onset autoinflammation and lipodystrophy to enable diagnosis and guide targeted JAK inhibitor therapy.

References

• Dermatology (Basel, Switzerland) • 2013 • A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. PMID:23942189
• Journal of pediatric hematology/oncology • 2015 • CANDLE syndrome: a recently described autoinflammatory syndrome. PMID:25036278
• European journal of pediatrics • 2016 • CANDLE syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature-a rare case with a novel mutation. PMID:26567544
• Pediatric rheumatology online journal • 2019 • Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome. PMID:31046790
• BMC medical genetics • 2020 • A Chinese case of Nakajo-Nishimura syndrome with novel compound heterozygous mutations of the PSMB8 gene. PMID:32513120
• Mediterranean journal of rheumatology • 2023 • Nakajo-Nishimura Syndrome: The First African Case. PMID:37654638
• Neuropathology and applied neurobiology • 2020 • Myositis with sarcoplasmic inclusions in Nakajo-Nishimura syndrome: a genetic inflammatory myopathy. PMID:32144790
• Arthritis and rheumatism • 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. PMID:21953331
• The Journal of clinical investigation • 2011 • A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. PMID:21881205
• Frontiers in immunology • 2015 • Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. PMID:26524591

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