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Haploinsufficiency of PSMD12 Causes Proteasome Dysfunction and Subclinical Autoinflammation.
Yan, Kai; Zhang, Jiahui; Lee, Pui Y; Tao, Panfeng; Wang, Jun; Wang, Shihao; Zhou, Qing; Dong, Minyue.
Afiliação
  • Yan K; Zhejiang University, Hangzhou, China.
  • Zhang J; Zhejiang University, Hangzhou, China.
  • Lee PY; Harvard Medical School, Boston, Massachusetts.
  • Tao P; Zhejiang University and Zhejiang University Medical Center, Hangzhou, China.
  • Wang J; Zhejiang University, Hangzhou, China.
  • Wang S; Zhejiang University, Hangzhou, China.
  • Zhou Q; Zhejiang University, Hangzhou, China.
  • Dong M; Zhejiang University, Hangzhou, China.
Arthritis Rheumatol ; 74(6): 1083-1090, 2022 06.
Article em En | MEDLINE | ID: mdl-35080150
OBJECTIVE: Proteasome-associated autoinflammatory syndrome (PRAAS) is caused by mutations affecting components of the proteasome and activation of the type I interferon (IFN) pathway. This study was undertaken to investigate the pathogenic mechanisms of a newly recognized type of PRAAS caused by PSMD12 haploinsufficiency. METHODS: Whole-exome sequencing was performed in members of a family with skin rash, congenital uveitis, and developmental delay. We performed functional studies to assess proteasome dysfunction and inflammatory signatures in patients, and single-cell RNA sequencing to further explore the spectrum of immune cell activation. RESULTS: A novel truncated variant in PSMD12 (c.865C>T, p.Arg289*) was identified in 2 family members. The impairment of proteasome function was found in peripheral blood mononuclear cells (PBMCs), as well as in PSMD12-knockdown HEK 293T cell lines. Moreover, we defined the inflammatory signatures in patient PBMCs and found elevated IFN signals, especially in monocytes, by single-cell RNA sequencing. CONCLUSION: These findings indicate that PSMD12 haploinsufficiency causes a set of inflammation signatures in addition to neurodevelopmental disorders. Our work expands the genotype and phenotype spectrum of PRAAS and suggests a bridge between the almost exclusively inflammatory phenotypes in the majority of PRAAS patients and the almost exclusively neurodevelopmental phenotypes in the previously reported Stankiewicz-Isidor syndrome.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complexo de Endopeptidases do Proteassoma / Haploinsuficiência Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Humans Idioma: En Revista: Arthritis Rheumatol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Complexo de Endopeptidases do Proteassoma / Haploinsuficiência Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Humans Idioma: En Revista: Arthritis Rheumatol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: China