RT Journal Article
T1 Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production.
A1 Brehm, Anja
A1 Liu, Yin
A1 Sheikh, Afzal
A1 Marrero, Bernadette
A1 Omoyinmi, Ebun
A1 Zhou, Qing
A1 Montealegre, Gina
A1 Biancotto, Angelique
A1 Reinhardt, Adam
A1 Almeida de Jesus, Adriana
A1 Pelletier, Martin
A1 Tsai, Wanxia L
A1 Remmers, Elaine F
A1 Kardava, Lela
A1 Hill, Suvimol
A1 Kim, Hanna
A1 Lachmann, Helen J
A1 Megarbane, Andre
A1 Chae, Jae Jin
A1 Brady, Jilian
A1 Castillo, Rhina D
A1 Brown, Diane
A1 Vera Casano, Angel
A1 Gao, Ling
A1 Chapelle, Dawn
A1 Huang, Yan
A1 Stone, Deborah
A1 Chen, Yongqing
A1 Sotzny, Franziska
A1 Lee, Chyi-Chia Richard
A1 Kastner, Daniel L
A1 Torrelo, Antonio
A1 Zlotogorski, Abraham
A1 Moir, Susan
A1 Gadina, Massimo
A1 McCoy, Phil
A1 Wesley, Robert
A1 Rother, Kristina
A1 Hildebrand, Peter W
A1 Brogan, Paul
A1 Krüger, Elke
A1 Aksentijevich, Ivona
A1 Goldbach-Mansky, Raphaela
K1 Células cultivadas
K1 Fibroblastos
K1 Regulación de la expresión génica
K1 Genotipo
K1 Enfermedades autoinflamatorias hereditarias
K1 Secuencia de aminoácidos
K1 Interferón de tipo I
K1 Modelos moleculares
K1 Chaperonas moleculares
K1 Datos de Secuencia Molecular
K1 Mutación
K1 Mutación de sentido erróneo
K1 Linaje
K1 Fenotipo
K1 Complejo de endopeptidasas de los proteasomas
K1 Conformación de proteínas
K1 Subunidades de proteínas
K1 Interferencia por ARN
K1 Alineación de secuencias
K1 Deleción de secuencias
K1 Homología de secuencias de aminoácidos
K1 Síndrome
K1 Transcripción genética
AB Autosomal recessive mutations in proteasome subunit β 8 (PSMB8), which encodes the inducible proteasome subunit β5i, cause the immune-dysregulatory disease chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE), which is classified as a proteasome-associated autoinflammatory syndrome (PRAAS). Here, we identified 8 mutations in 4 proteasome genes, PSMA3 (encodes α7), PSMB4 (encodes β7), PSMB9 (encodes β1i), and proteasome maturation protein (POMP), that have not been previously associated with disease and 1 mutation in PSMB8 that has not been previously reported. One patient was compound heterozygous for PSMB4 mutations, 6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit, and 1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS. Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity. Moreover, defects in proteasome formation and function were recapitulated by siRNA-mediated knockdown of the respective subunits in primary fibroblasts from healthy individuals. Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype. Additionally, chemical proteasome inhibition or progressive depletion of proteasome subunit gene transcription with siRNA induced transcription of type I IFN genes in healthy control cells. Our results provide further insight into CANDLE genetics and link global proteasome dysfunction to increased type I IFN production.
PB American Society for Clinical Investigation
SN 0021-9738
YR 2015
FD 2015-11-02
LK http://hdl.handle.net/10668/2213
UL http://hdl.handle.net/10668/2213
LA en
NO Brehm A, Liu Y, Sheikh A, Marrero B, Omoyinmi E, Zhou Q, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J. Clin. Invest. 2015; 125(11):4196-211
NO Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't;Erratium en J Clin Invest. 2016 Feb 1;126(2):795. doi: 10.1172/JCI86020: https://www.jci.org/articles/view/86020
DS RISalud
RD Apr 10, 2025