Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production

Anja Brehm, Yin Liu, Afzal Sheikh, Bernadette Marrero, Ebun Omoyinmi, Qing Zhou, Gina Montealegre, Angelique Biancotto, Adam L Reinhardt, Adriana Almeida De Jesus, Martin Pelletier, Wanxia L. Tsai, Elaine F. Remmers, Lela Kardava, Suvimol Hill, Hanna Kim, Helen J. Lachmann, Andre Megarbane, Jae Jin Chae, Jilian Brady & 23 others Rhina D. Castillo, Diane Brown, Angel Vera Casano, Ling Gao, Dawn Chapelle, Yan Huang, Deborah Stone, Yongqing Chen, Franziska Sotzny, Chyi Chia Richard Lee, Daniel L. Kastner, Antonio Torrelo, Abraham Zlotogorski, Susan Moir, Massimo Gadina, Phil McCoy, Robert Wesley, Kristina Rother, Peter W. Hildebrand, Paul Brogan, Elke Krüger, Ivona Aksentijevich, Raphaela Goldbach-Mansky

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)4196-4211
Number of pages16
JournalJournal of Clinical Investigation
Volume125
Issue number11
DOIs
StatePublished - Nov 2 2015

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Proteasome Endopeptidase Complex
Mutation
Small Interfering RNA
Genes
Lipodystrophy
Inheritance Patterns
Protein Folding
Immune System Diseases
Missense Mutation
Transcriptome
Skin Diseases
Fibroblasts

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brehm, A., Liu, Y., Sheikh, A., Marrero, B., Omoyinmi, E., Zhou, Q., ... Goldbach-Mansky, R. (2015). Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production. Journal of Clinical Investigation, 125(11), 4196-4211. https://doi.org/10.1172/JCI81260

Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production. / Brehm, Anja; Liu, Yin; Sheikh, Afzal; Marrero, Bernadette; Omoyinmi, Ebun; Zhou, Qing; Montealegre, Gina; Biancotto, Angelique; Reinhardt, Adam L; De Jesus, Adriana Almeida; Pelletier, Martin; Tsai, Wanxia L.; Remmers, Elaine F.; Kardava, Lela; Hill, Suvimol; Kim, Hanna; Lachmann, Helen J.; Megarbane, Andre; Chae, Jae Jin; Brady, Jilian; Castillo, Rhina D.; Brown, Diane; Casano, Angel Vera; Gao, Ling; Chapelle, Dawn; Huang, Yan; Stone, Deborah; Chen, Yongqing; Sotzny, Franziska; Lee, Chyi Chia Richard; Kastner, Daniel L.; Torrelo, Antonio; Zlotogorski, Abraham; Moir, Susan; Gadina, Massimo; McCoy, Phil; Wesley, Robert; Rother, Kristina; Hildebrand, Peter W.; Brogan, Paul; Krüger, Elke; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela.

In: Journal of Clinical Investigation, Vol. 125, No. 11, 02.11.2015, p. 4196-4211.

Research output: Contribution to journalArticle

Brehm, A, Liu, Y, Sheikh, A, Marrero, B, Omoyinmi, E, Zhou, Q, Montealegre, G, Biancotto, A, Reinhardt, AL, De Jesus, AA, Pelletier, M, Tsai, WL, Remmers, EF, Kardava, L, Hill, S, Kim, H, Lachmann, HJ, Megarbane, A, Chae, JJ, Brady, J, Castillo, RD, Brown, D, Casano, AV, Gao, L, Chapelle, D, Huang, Y, Stone, D, Chen, Y, Sotzny, F, Lee, CCR, Kastner, DL, Torrelo, A, Zlotogorski, A, Moir, S, Gadina, M, McCoy, P, Wesley, R, Rother, K, Hildebrand, PW, Brogan, P, Krüger, E, Aksentijevich, I & Goldbach-Mansky, R 2015, 'Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production', Journal of Clinical Investigation, vol. 125, no. 11, pp. 4196-4211. https://doi.org/10.1172/JCI81260
Brehm, Anja ; Liu, Yin ; Sheikh, Afzal ; Marrero, Bernadette ; Omoyinmi, Ebun ; Zhou, Qing ; Montealegre, Gina ; Biancotto, Angelique ; Reinhardt, Adam L ; De Jesus, Adriana Almeida ; Pelletier, Martin ; Tsai, Wanxia L. ; Remmers, Elaine F. ; Kardava, Lela ; Hill, Suvimol ; Kim, Hanna ; Lachmann, Helen J. ; Megarbane, Andre ; Chae, Jae Jin ; Brady, Jilian ; Castillo, Rhina D. ; Brown, Diane ; Casano, Angel Vera ; Gao, Ling ; Chapelle, Dawn ; Huang, Yan ; Stone, Deborah ; Chen, Yongqing ; Sotzny, Franziska ; Lee, Chyi Chia Richard ; Kastner, Daniel L. ; Torrelo, Antonio ; Zlotogorski, Abraham ; Moir, Susan ; Gadina, Massimo ; McCoy, Phil ; Wesley, Robert ; Rother, Kristina ; Hildebrand, Peter W. ; Brogan, Paul ; Krüger, Elke ; Aksentijevich, Ivona ; Goldbach-Mansky, Raphaela. / Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 11. pp. 4196-4211.
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title = "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production",
abstract = "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.",
author = "Anja Brehm and Yin Liu and Afzal Sheikh and Bernadette Marrero and Ebun Omoyinmi and Qing Zhou and Gina Montealegre and Angelique Biancotto and Reinhardt, {Adam L} and {De Jesus}, {Adriana Almeida} and Martin Pelletier and Tsai, {Wanxia L.} and Remmers, {Elaine F.} and Lela Kardava and Suvimol Hill and Hanna Kim and Lachmann, {Helen J.} and Andre Megarbane and Chae, {Jae Jin} and Jilian Brady and Castillo, {Rhina D.} and Diane Brown and Casano, {Angel Vera} and Ling Gao and Dawn Chapelle and Yan Huang and Deborah Stone and Yongqing Chen and Franziska Sotzny and Lee, {Chyi Chia Richard} and Kastner, {Daniel L.} and Antonio Torrelo and Abraham Zlotogorski and Susan Moir and Massimo Gadina and Phil McCoy and Robert Wesley and Kristina Rother and Hildebrand, {Peter W.} and Paul Brogan and Elke Kr{\"u}ger and Ivona Aksentijevich and Raphaela Goldbach-Mansky",
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T1 - Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type i IFN production

AU - Brehm, Anja

AU - Liu, Yin

AU - Sheikh, Afzal

AU - Marrero, Bernadette

AU - Omoyinmi, Ebun

AU - Zhou, Qing

AU - Montealegre, Gina

AU - Biancotto, Angelique

AU - Reinhardt, Adam L

AU - De Jesus, Adriana Almeida

AU - Pelletier, Martin

AU - Tsai, Wanxia L.

AU - Remmers, Elaine F.

AU - Kardava, Lela

AU - Hill, Suvimol

AU - Kim, Hanna

AU - Lachmann, Helen J.

AU - Megarbane, Andre

AU - Chae, Jae Jin

AU - Brady, Jilian

AU - Castillo, Rhina D.

AU - Brown, Diane

AU - Casano, Angel Vera

AU - Gao, Ling

AU - Chapelle, Dawn

AU - Huang, Yan

AU - Stone, Deborah

AU - Chen, Yongqing

AU - Sotzny, Franziska

AU - Lee, Chyi Chia Richard

AU - Kastner, Daniel L.

AU - Torrelo, Antonio

AU - Zlotogorski, Abraham

AU - Moir, Susan

AU - Gadina, Massimo

AU - McCoy, Phil

AU - Wesley, Robert

AU - Rother, Kristina

AU - Hildebrand, Peter W.

AU - Brogan, Paul

AU - Krüger, Elke

AU - Aksentijevich, Ivona

AU - Goldbach-Mansky, Raphaela

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N2 - 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.

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