Dataset Information

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

ABSTRACT: Autosomal recessive mutations in proteasome subunit ? 8 (PSMB8), which encodes the inducible proteasome subunit ?5i, 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 ?7), PSMB4 (encodes ?7), PSMB9 (encodes ?1i), 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.

SUBMITTER: Brehm A

PROVIDER: S-EPMC4639987 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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

Brehm Anja A Liu Yin Y Sheikh Afzal A Marrero Bernadette B Omoyinmi Ebun E Zhou Qing Q Montealegre Gina G Biancotto Angelique A Reinhardt Adam A Almeida de Jesus Adriana A Pelletier Martin M Tsai Wanxia L WL Remmers Elaine F EF Kardava Lela L Hill Suvimol S Kim Hanna H Lachmann Helen J HJ Megarbane Andre A Chae Jae Jin JJ Brady Jilian J Castillo Rhina D RD Brown Diane D Casano Angel Vera AV Gao Ling L Chapelle Dawn D Huang Yan Y Stone Deborah D Chen Yongqing Y Sotzny Franziska F Lee Chyi-Chia Richard CC Kastner Daniel L DL Torrelo Antonio A Zlotogorski Abraham A Moir Susan S Gadina Massimo M McCoy Phil P Wesley Robert R Rother Kristina I KI Hildebrand Peter W PW Brogan Paul P Krüger Elke E Aksentijevich Ivona I Goldbach-Mansky Raphaela R

The Journal of clinical investigation 20151020 11

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 ...[more]

PMID: 26524591

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Project description:Glycine receptors (GlyRs) containing the α2 subunit govern cell fate, neuronal migration and synaptogenesis in the developing cortex and spinal cord. Rare missense variants and microdeletions in the X-linked GlyR α2 subunit gene (GLRA2) have been associated with human autism spectrum disorder (ASD), where they typically cause a loss-of-function via protein truncation, reduced cell-surface trafficking and/or reduced glycine sensitivity (e.g., GLRA2Δex8-9 and extracellular domain variants p.N109S and p.R126Q). However, the GlyR α2 missense variant p.R323L in the intracellular M3-M4 domain results in a gain-of-function characterized by slower synaptic decay times, longer duration active periods and increases in channel conductance. This study reports the functional characterization of four missense variants in GLRA2 associated with ASD or developmental disorders (p.V-22L, p.N38K, p.K213E, p.T269M) using a combination of bioinformatics, molecular dynamics simulations, cellular models of GlyR trafficking and electrophysiology in artificial synapses. The GlyR α2V-22L variant resulted in altered predicted signal peptide cleavage and a reduction in cell-surface expression, suggestive of a partial loss-of-function. Similarly, GlyR α2N38K homomers showed reduced cell-surface expression, a reduced affinity for glycine and a reduced magnitude of IPSCs in artificial synapses. By contrast, GlyR α2K213E homomers showed a slight reduction in cell-surface expression, but IPSCs were larger, with faster rise/decay times, suggesting a gain-of-function. Lastly, GlyR α2T269M homomers exhibited a high glycine sensitivity accompanied by a substantial leak current, suggestive of an altered function that could dramatically enhance glycinergic signaling. These results may explain the heterogeneity of clinical phenotypes associated with GLRA2 mutations and reveal that missense variants can result in a loss, gain or alteration of GlyR α2 function. In turn, these GlyR α2 missense variants are likely to either negatively or positively deregulate cortical progenitor homeostasis and neuronal migration in the developing brain, leading to changes in cognition, learning, and memory.

Dataset Information

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

Publications

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

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