Proteasome-Associated Autoinflammatory Syndrome

Mendelian MONDO:0009726 Pathograph 20 Show in embeddings browser Autoinflammatory diseases Interferonopathies Inborn errors of immunity

Proteasome-associated autoinflammatory syndrome (PRAAS) is a genetically heterogeneous Mendelian type I interferonopathy caused by loss-of-function defects in proteasome or immunoproteasome subunits and proteasome assembly factors. The disease spectrum encompasses the historically named CANDLE, Nakajo-Nishimura, and JMP syndromes and is characterized by proteotoxic stress, chronic interferon activation, inflammatory skin disease, progressive lipodystrophy, joint contractures, and systemic inflammatory complications.

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3
Inheritance
6
Pathophys.
7
Phenotypes
20
Pathograph
8
Genes
2
Medical Actions
6
Subtypes
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC DERMATOLOGY GENETICS ENVIRONMENT DISEASE
IUIS Category
autoinflammatory syndrome
👪

Inheritance

3
Autosomal recessive (classic CANDLE/PRAAS) HP:0000007
The founding form of the disease: biallelic PSMB8 variants causing CANDLE. This remains the commonest architecture and is the reference point the dominant and digenic patterns below were recognized against.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26524591 SUPPORT Human Clinical
"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)"
States the recessive PSMB8 architecture of classic CANDLE explicitly.
Autosomal dominant HP:0000006
A single heterozygous POMP variant is sufficient in at least one reported patient, establishing a dominant arm alongside the recessive and digenic ones.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:26524591 SUPPORT Human Clinical
"1 patient was heterozygous for a POMP mutation, thus establishing a digenic and autosomal dominant inheritance pattern of PRAAS"
The same sentence that establishes the digenic pattern names the dominant one; both are asserted by the discovery study.
Digenic (inducible plus constitutive subunit) HP:0010984
A distinct and mechanistically specific two-locus architecture: six patients from four families each carried a heterozygous missense variant in an INDUCIBLE proteasome subunit together with a variant in a CONSTITUTIVE subunit. The two lesions are not interchangeable partners drawn from one gene set - they hit the two different proteasome populations, which is the sense in which the discovery study titled the mechanism additive loss of function. Its functional work showed the mutations converging, by varied routes, on proteasome activity; the abstract does not decompose the digenic phenotype against either subunit class alone, so no such comparison is asserted here. Because the Inheritance class has no genes slot, the genes in which that study reported mutations are named: PSMA3, PSMB4, PSMB9, PSMB8 and POMP - the inducible subunits among them being PSMB8 and PSMB9 and the constitutive ones PSMA3 and PSMB4. Note the abstract does not say which pairs occurred in which digenic family, so the per-family combinations are deliberately not stated. A 2026 report extends the pattern to PSMA6 (PMID:41205671), which is not curated here because no abstract is available to quote.
Digenic inheritance
Show evidence (2 references)
PMID:26524591 SUPPORT Human Clinical
"6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit"
Reports the two-locus genotype and its recurrence across four independent families, which is what distinguishes it from a single-family observation. Note the abstract states the subunit CLASSES that pair, not the individual genes per family.
PMID:38578475 SUPPORT Other
"Proteasome-associated diseases have complex inheritance, including monogenic, digenic and oligogenic disorders and can be dominantly or recessively inherited."
A 2024 review confirming digenic and oligogenic inheritance as an established part of the proteasome-disease spectrum, not a single report.
◆

Subtypes

6
PRAAS1 (PSMB8) MONDO:0054698
PSMB8 hgnc:9545 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PSMB8 (hgnc:9545). hgnc:9545 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
The PSMB8-associated form and the reference presentation of the umbrella disease. Recessive variants in the inducible beta-5i catalytic subunit cause CANDLE, and the same gene underlies the JMP presentation curated in this entry. Per-gene detail is in the PSMB8 record of the genetic section.
Show evidence (1 reference)
PMID:21129723 SUPPORT Human Clinical
"We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing."
The discovery study establishes PSMB8 as causative for the JMP presentation, one of the historically named phenotypes this subtype row covers.
PRAAS2 (POMP) MONDO:0054700
POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The POMP-associated form, distinguished by early-onset combined immunodeficiency alongside the inflammatory neutrophilic dermatosis and autoimmunity. Its discovery study named it POMP-related autoinflammation and immune dysregulation disease (PRAID). PRAAS2 is the name MONDO:0054700 carries as a synonym, mapped to OMIM:618048.
Show evidence (3 references)
PMID:38111302 SUPPORT Human Clinical
"Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is characterized by early onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity."
Names the PRAAS2 entity and its defining features, which is what this subtype row asserts.
PMID:38111302 SUPPORT Human Clinical
"A novel de novo frameshift proteasome maturation protein (POMP) mutation (c.333delT (p.t111fs)) was detected, confirming the diagnosis."
Ties the PRAAS2 diagnosis to a de novo POMP frameshift variant in a further, independent patient.
PMID:29805043 SUPPORT Human Clinical
"Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity."
The discovery study's own naming of the POMP entity, and the clinical constellation that distinguishes it inside the PRAAS spectrum.
PRAAS3 (PSMB4) MONDO:0054699
PSMB4 hgnc:9541 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PSMB4 (hgnc:9541). hgnc:9541 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
The PSMB4-associated form. PSMB4 was one of four proteasome genes newly linked to CANDLE/PRAAS by the additive loss-of-function study, which reported it both as a compound-heterozygous cause in one patient and as a constitutive subunit participating in digenic genotypes.
Show evidence (1 reference)
PMID:26524591 SUPPORT Human Clinical
"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"
The study that first associated PSMB4 with the disease, naming the subunit it encodes.
PRAAS4 (PSMG2) MONDO:0030931
PSMG2 hgnc:24929 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PSMG2 (hgnc:24929). hgnc:24929 is a gene from the HUGO Gene Nomenclature Committee.
The PSMG2-associated form, reported in a patient with CANDLE features who also had autoimmune hemolytic anemia. PSMG2 encodes the PAC2 assembly chaperone, making this the second chaperone-defect form alongside PRAAS2.
Show evidence (1 reference)
PMID:30664889 SUPPORT Human Clinical
"Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE."
Establishes PSMG2 as a cause of the CANDLE presentation curated by this entry.
PRAAS5 (PSMB10) MONDO:0030924
PSMB10 hgnc:9538 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PSMB10 (hgnc:9538). hgnc:9538 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
The PSMB10-associated form. Compound-heterozygous PSMB10 variants were found in three unrelated Brazilian patients with a CANDLE/PRAAS phenotype, and the variants were shown to block incorporation of the beta-2i subunit into mature proteasomes.
Show evidence (2 references)
PMID:37600812 SUPPORT Human Clinical
"Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10"
Names PSMB10 as an established CANDLE/PRAAS gene and reports the genotypes this row is keyed on.
PMID:37600812 SUPPORT In Vitro
"All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
Functional evidence that the reported variants act by impairing subunit expression or incorporation, the mechanism this entry models downstream.
PRAAS6 (PSMB9) MONDO:0968983
PSMB9 hgnc:9546 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in PSMB9 (hgnc:9546). hgnc:9546 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance
The PSMB9-associated form. This row is the most contested in the series. The two reported patients carried the same de novo heterozygous PSMB9 G156D variant and had pulmonary hypertension and combined immunodeficiency without lipoatrophy, and their authors proposed a separate category, PRAAS-ID, rather than a PRAAS subtype. MONDO:0968983 instead labels it proteasome-associated autoinflammatory syndrome 6, maps it to OMIM:620796 and places it directly under this umbrella, which is the nosology this row follows; the countervailing argument is recorded here and in the entry notes.
Show evidence (3 references)
PMID:34819510 SUPPORT Human Clinical
"In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms."
Supports PSMB9 variants producing a PRAAS-like disease while naming the two features that separate it from the rest of the spectrum.
PMID:34819510 REFUTE Human Clinical
"We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study."
Cited against this row's placement: the reporting authors argue the PSMB9 entity is a separate category rather than a PRAAS subtype.
PMID:26524591 SUPPORT Human Clinical
"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"
PSMB9 was first linked to CANDLE/PRAAS in this cohort, which is the basis for treating the gene as part of the umbrella spectrum.
⚙

Pathophysiology

6
Proteasome Subunit Loss of Function
Inherited or de novo loss-of-function defects in subunits of the proteasome initiate one of the two genetic routes into the PRAAS cascade. The inducible immunoproteasome catalytic subunits beta-5i (PSMB8), beta-1i (PSMB9) and beta-2i (PSMB10) and the constitutive components beta-7 (PSMB4) and alpha-7 (PSMA3) are the subunits reported in this disease. The reported variants act by reducing subunit expression, blocking propeptide processing, or preventing incorporation into the mature particle.
PSMB8 hgnc:9545 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSMB8 (hgnc:9545). hgnc:9545 is a gene from the HUGO Gene Nomenclature Committee. PSMA3 hgnc:9532 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSMA3 (hgnc:9532). hgnc:9532 is a gene from the HUGO Gene Nomenclature Committee. PSMB9 hgnc:9546 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSMB9 (hgnc:9546). hgnc:9546 is a gene from the HUGO Gene Nomenclature Committee. PSMB10 hgnc:9538 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSMB10 (hgnc:9538). hgnc:9538 is a gene from the HUGO Gene Nomenclature Committee. PSMB4 hgnc:9541 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSMB4 (hgnc:9541). hgnc:9541 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Proteasome Biogenesis and Activity
Show evidence (2 references)
PMID:31827472 SUPPORT Other
"By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively."
Establishes the initiating lesion in PRAAS as loss of proteasome or proteasome-assembly function, and separates the subunit genes from the assembly-factor genes.
PMID:37600812 SUPPORT In Vitro
"All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
Functional evidence for the allelic mechanisms named in this node's description.
Proteasome Assembly Chaperone Loss of Function
The second genetic route into the cascade. Defects in the chaperones that build the proteasome rather than in the proteasome subunits themselves: POMP, which incorporates the catalytic subunits into the assembling particle, and PSMG2, which encodes the PAC2 assembly chaperone. This arm is separated from the proteasome-subunit arm because the lesion is in the assembly machinery and not in the particle it assembles.
POMP hgnc:20330 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee. PSMG2 hgnc:24929 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves PSMG2 (hgnc:24929). hgnc:24929 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Impaired Proteasome Biogenesis and Activity Loss of chaperone function leaves the catalytic subunits unincorporated, so mature proteasome is not formed.
Show evidence (3 references)
PMID:31827472 SUPPORT Other
"By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively."
Names POMP and PSMG2 as the assembly-factor causes, which is the gene set bound to this node.
PMID:29805043 SUPPORT BACKGROUND Other
"Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome."
States the chaperone role that makes POMP loss an assembly defect rather than a catalytic defect.
PMID:30664889 SUPPORT Human Clinical
"Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE."
Supports the second chaperone gene bound to this node as a cause of the disease.
Impaired Proteasome Biogenesis and Activity
PRAAS variants disrupt proteasome subunit expression, assembly, and mature proteasome function, reducing proteolytic capacity.
proteasome-mediated protein degradation GO:0043161 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased proteasome-mediated protein degradation, annotated with proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161). GO:0043161 is a biological process from the Gene Ontology.
Downstream
Proteotoxic and Endoplasmic Reticulum Stress
Show evidence (2 references)
PMID:26524591 SUPPORT In Vitro
"Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity."
Functional studies show that PRAAS-associated variants impair proteasome assembly and catalytic output.
PMID:37600812 SUPPORT In Vitro
"All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
Additional contemporary functional evidence links newly reported PRAAS variants to defective mature proteasome formation.
Proteotoxic and Endoplasmic Reticulum Stress
Impaired proteasome function causes accumulation of ubiquitinated or misfolded proteins, engaging stress pathways including the unfolded protein response.
response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology.
Downstream
PKR-Mediated Type I Interferon Signaling
Show evidence (2 references)
PMID:31827472 SUPPORT Other
"Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature."
Review abstract directly links proteasome defects to ubiquitinated-protein accumulation and the interferon signature.
PMID:31827472 SUPPORT Other
"One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress)."
Supports ER stress and UPR engagement as a mechanistic bridge between proteasome dysfunction and interferon activation.
PKR-Mediated Type I Interferon Signaling
Protein kinase R senses proteotoxic stress in PRAAS and amplifies type I interferon and inflammatory signaling.
type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased type I interferon-mediated signaling pathway (GO:0060337). GO:0060337 is a biological process from the Gene Ontology.
Downstream
Persistent Interferon Signature
Show evidence (2 references)
PMID:35148201 SUPPORT In Vitro
"Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress."
Mechanistic study identifies PKR as the sensor that connects proteasome dysfunction to inflammatory signaling.
PMID:35148201 SUPPORT In Vitro
"under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24)."
Abstract-level evidence specifies the proximate signal sensed by PKR during proteasome dysfunction.
Persistent Interferon Signature
Patient immune and stromal cells show a sustained interferon-response program that remains a central molecular hallmark across PRAAS genotypes.
monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
Downstream
Periodic fever Recurrent fever driven by the sustained interferon response rather than by an inflammasome cycle — which is what distinguishes this from the classic periodic fever syndromes.
Chilblains Acral violaceous lesions, the characteristic cutaneous sign of a type I interferonopathy.
Panniculitis Inflammation of subcutaneous fat.
Lipodystrophy Progressive loss of subcutaneous fat, which in this disease follows the panniculitis rather than occurring independently — the sequence is inflammation first, then loss.
Skeletal muscle atrophy Progressive muscle wasting, part of the same progressive-loss phenotype.
Joint contracture Contractures developing as the inflammatory and atrophic process crosses joints.
Microcytic anemia Anaemia of chronic inflammation, microcytic here.
Show evidence (2 references)
PMID:26524591 SUPPORT Human Clinical
"Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype."
Demonstrates that the interferon program is a shared downstream phenotype across genetically diverse PRAAS cases.
PMID:21953331 SUPPORT Human Clinical
"Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders."
Early CANDLE cohort data confirm monocyte interferon-pathway activation as a core disease feature.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Proteasome-Associated Autoinflammatory Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

7
Blood 1
Microcytic anemia HP:0001935 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is microcytic anemia (HP:0001935). HP:0001935 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21129723 SUPPORT Human Clinical
"We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
Discovery study supports chronic microcytic anemia as a characteristic hematologic feature within PRAAS.
Immune 2
Chilblains HP:0009710 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is pernio-like rash, annotated with Chilblains (HP:0009710). HP:0009710 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31576159 SUPPORT Other
"Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers."
The same review abstract supports pernio-like acral skin inflammation as part of the PRAAS phenotype spectrum.
Panniculitis HP:0012490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is panniculitis (HP:0012490). HP:0012490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21129723 SUPPORT Human Clinical
"We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
JMP discovery abstract directly supports panniculitis-associated adipose inflammation in PSMB8-related PRAAS.
Metabolism 1
Periodic fever HP:0032323 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is periodic fever (HP:0032323). HP:0032323 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31576159 SUPPORT Other
"Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers."
Review abstract identifies periodic fever as a canonical feature of Nakajo-Nishimura syndrome within the PRAAS spectrum.
Musculoskeletal 3
Lipodystrophy HP:0009125 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is lipodystrophy (HP:0009125). HP:0009125 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:31046790 SUPPORT Human Clinical
"Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive."
Case-report abstract confirms progressive lipodystrophy as a key CANDLE manifestation within PRAAS.
PMID:21129723 SUPPORT Human Clinical
"We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
Discovery study supports lipodystrophy as a defining feature in the JMP presentation of the PRAAS spectrum.
Joint contracture HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21129723 SUPPORT Human Clinical
"We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
The JMP discovery abstract directly anchors joint contracture as a core spectrum phenotype.
Skeletal muscle atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:21129723 SUPPORT Human Clinical
"We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
Supports muscle atrophy as a defining feature of a canonical PSMB8-related PRAAS presentation.
🧬

Genetic Associations

8
Proteasome subunit and assembly-factor loss-of-function variants (Causative)
Show evidence (2 references)
PMID:31827472 SUPPORT Other
"By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively."
Review abstract defines the umbrella disease genetically and anchors the core subunit and assembly-factor gene set.
PMID:37600812 SUPPORT Human Clinical
"Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M."
Recent case-series evidence expands the PRAAS gene spectrum beyond the earlier canonical set.
PSMB8 (Recurrent causative gene)
Gene: PSMB8 hgnc:9545 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSMB8 (hgnc:9545). hgnc:9545 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:21129723 SUPPORT Human Clinical
"We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing."
Discovery study establishes PSMB8 as a causative gene for one of the canonical PRAAS presentations.
PMID:31046790 SUPPORT Human Clinical
"Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome."
Case-report abstract confirms PSMB8 as the recurrent disease gene in CANDLE, another historically named PRAAS phenotype.
PSMA3 (Constitutive-subunit partner in the digenic architecture)
Gene: PSMA3 hgnc:9532 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSMA3 (hgnc:9532). hgnc:9532 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: COOPERATING
Show evidence (2 references)
PMID:26524591 SUPPORT Human Clinical
"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"
First association of PSMA3 with the disease, and the subunit it encodes.
PMID:26524591 SUPPORT Human Clinical
"6 patients from 4 families were heterozygous for a missense mutation in 1 inducible proteasome subunit and a mutation in a constitutive proteasome subunit"
Reports the digenic pairing of a constitutive subunit, the class PSMA3 belongs to, with an inducible one.
POMP (Assembly-chaperone cause of the PRAAS2 form)
Gene: POMP hgnc:20330 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is POMP (hgnc:20330). hgnc:20330 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:29805043 SUPPORT Human Clinical
"Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity."
Establishes POMP as the cause of a distinct entity within this spectrum in two unrelated individuals.
PMID:29805043 SUPPORT Human Clinical
"de novo heterozygous frameshift variants in the penultimate exon of POMP escape nonsense-mediated mRNA decay (NMD) and result in a truncated protein that perturbs proteasome assembly by a dominant-negative mechanism"
Gives the allelic mechanism recorded in this record's notes.
PSMB4 (Structural-subunit cause of the PRAAS3 form and digenic partner)
Gene: PSMB4 hgnc:9541 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSMB4 (hgnc:9541). hgnc:9541 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:26524591 SUPPORT Human Clinical
"One patient was compound heterozygous for PSMB4 mutations"
The biallelic PSMB4 genotype that defines this form.
PMID:26524591 SUPPORT Human Clinical
"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"
First association of PSMB4 with the disease, and the subunit it encodes.
PSMG2 (Assembly-chaperone cause of the PRAAS4 form)
Gene: PSMG2 hgnc:24929 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSMG2 (hgnc:24929). hgnc:24929 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (1 reference)
PMID:30664889 SUPPORT Human Clinical
"Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE."
Establishes PSMG2 as a cause of the CANDLE presentation this entry curates.
PSMB10 (Catalytic-subunit cause of the PRAAS5 form)
Gene: PSMB10 hgnc:9538 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSMB10 (hgnc:9538). hgnc:9538 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:37600812 SUPPORT Human Clinical
"Four patients were compound heterozygous for novel pathogenic variants in the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10"
Names PSMB10 among the established disease genes and reports the genotypes.
PMID:37600812 SUPPORT In Vitro
"All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
Functional support for the incorporation defect described in these notes.
PSMB9 (Catalytic-subunit cause of the PRAAS6 form)
Gene: PSMB9 hgnc:9546 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PSMB9 (hgnc:9546). hgnc:9546 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (2 references)
PMID:34819510 SUPPORT Human Clinical
"Here we report a de novo heterozygous missense variant of the PSMB9 proteasome subunit gene in two unrelated Japanese infants resulting in amino acid substitution of the glycine (G) by aspartic acid (D) at position 156 of the encoded protein β1i."
The gene, the recurrent variant and the de novo heterozygous architecture.
PMID:34819510 SUPPORT In Vitro
"Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation."
Gives the structural mechanism by which the variant blocks proteasome formation, the node this gene is wired to.
💊

Medical Actions

2
Baricitinib therapy
Action: targeted therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is targeted therapy (NCIT:C93352). NCIT:C93352 is a clinical intervention from the NCI Thesaurus. Ontology label: Targeted Therapy NCIT:C93352
Agent: baricitinib CHEBI:95341 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baricitinib (CHEBI:95341). CHEBI:95341 is a therapeutic agent from Chemical Entities of Biological Interest.
JAK1/2 inhibition with baricitinib can suppress interferon-driven disease activity in PRAAS, but dose reductions may precipitate rebound flares.
Show evidence (2 references)
PMID:38653530 SUPPORT Human Clinical
"Patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid arthritis."
PRAAS-specific cohort data support baricitinib as an effective mechanism-based therapy and show its exposure-response dependence.
PMID:31046790 SUPPORT Human Clinical
"We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth."
Independent case evidence supports clinically meaningful baricitinib benefit in CANDLE/PRAAS.
Anifrolumab therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anifrolumab NCIT:C166658 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anifrolumab (NCIT:C166658). NCIT:C166658 is a therapeutic agent from the NCI Thesaurus.
IFNAR1 blockade with anifrolumab is an emerging treatment option for type I interferonopathies and has early supportive evidence in CANDLE/PRAAS.
Show evidence (2 references)
PMID:39441221 SUPPORT Human Clinical
"Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone."
The case-series abstract directly includes one CANDLE patient and supports IFNAR1 blockade as a rational add-on strategy.
PMID:39441221 SUPPORT Human Clinical
"Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies."
Supports the specific therapeutic rationale of directly suppressing IFN-I signaling in interferonopathy-spectrum disease.
{ }

Source YAML

click to show 
name: Proteasome-Associated Autoinflammatory Syndrome
creation_date: "2026-04-14T05:24:49Z"
category: Mendelian
synonyms:
- PRAAS
- proteasome disability syndrome
- CANDLE syndrome
- Nakajo-Nishimura syndrome
- JMP syndrome
- autoinflammation-lipodystrophy-dermatosis syndrome
description: >
  Proteasome-associated autoinflammatory syndrome (PRAAS) is a genetically
  heterogeneous Mendelian type I interferonopathy caused by loss-of-function
  defects in proteasome or immunoproteasome subunits and proteasome assembly
  factors. The disease spectrum encompasses the historically named CANDLE,
  Nakajo-Nishimura, and JMP syndromes and is characterized by proteotoxic
  stress, chronic interferon activation, inflammatory skin disease,
  progressive lipodystrophy, joint contractures, and systemic inflammatory
  complications.
disease_term:
  preferred_term: proteasome-associated autoinflammatory syndrome
  term:
    id: MONDO:0009726
    label: proteosome-associated autoinflammatory syndrome
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: DERMATOLOGY
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  iuis_category:
    classification_value: autoinflammatory syndrome
    notes: >-
      IUIS 2022 phenotypic classification (Tangye et al., PMID:35748970), Table 7
      "Autoinflammatory disorders", section 3 "Non-Inflammasome Related
      Conditions", the PSMB8 and PSMG2 CANDLE rows. The table's text extraction
      fuses the end of the PSMB8 associated-features cell onto the start of the
      disease name in the next row, giving "feversCANDLE", so the quoted snippets
      stop at the cell boundary. IUIS marks the PSMB8 row with an asterisk whose
      footnote names PSMB4, PSMB9, PSMA3 and POMP as further proposed causes of
      the same CANDLE phenotype, which is the spectrum this umbrella entry
      curates.
    evidence:
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "PSMB8* AR and AD 256040 Keratinocytes, B cell adipose cells Contractures, panniculitis, ICC"
      explanation: >-
        The IUIS Table 7 row places the PSMB8 proteasome defect, with OMIM 256040
        and its contracture and panniculitis phenotype, among the
        autoinflammatory disorders.
    - reference: PMID:35748970
      reference_title: "Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) PSMG2 AR"
      explanation: >-
        The same Table 7 block names the disease CANDLE and adds the PSMG2
        assembly-factor genotype, confirming that the proteasome and
        assembly-factor spectrum curated here is one autoinflammatory table
        entry.
parents:
- Autoinflammatory diseases
- Interferonopathies
- Inborn errors of immunity
notes: >
  This disease-level entry uses the umbrella name PRAAS for the shared
  proteasome/immunoproteasome interferonopathy spectrum. The literature also
  uses CANDLE syndrome, Nakajo-Nishimura syndrome, and JMP syndrome for
  partially overlapping presentations within that spectrum, so those labels
  are retained as synonyms rather than treated as separate umbrella disorders
  here. MONDO:0009726 is the ontology anchor for the umbrella disease, but its
  canonical label is misspelled as "proteosome-associated autoinflammatory
  syndrome"; the entry name and preferred_term use the standard "proteasome"
  spelling while term.label follows MONDO exactly for validation.
  The OMIM-numbered forms PRAAS1 to PRAAS6 are curated as has_subtypes rows, each
  bound to its own MONDO class and to the gene reported for it. Two of the six sit
  at the edge of the umbrella. PRAAS2 was named POMP-related autoinflammation and
  immune dysregulation disease by its discovery study, and PRAAS6 was reported with
  an explicit proposal that it be treated as a separate category, PRAAS-ID, rather
  than as a PRAAS subtype, because the two patients had pulmonary hypertension and
  combined immunodeficiency without lipoatrophy. Both are kept as subtype rows here
  because MONDO places their classes directly under this umbrella and maps each to
  its own OMIM concept, and the countervailing argument is carried as evidence on
  the PRAAS6 row.
  The two genetic routes into the cascade are separated in the pathograph: the
  subunit genes are bound to Proteasome Subunit Loss of Function and the assembly
  chaperones POMP and PSMG2 to Proteasome Assembly Chaperone Loss of Function, both
  feeding Impaired Proteasome Biogenesis and Activity.
review_notes: >
  Initial disease-level curation for issue 1276. Emphasis was placed on
  spectrum-aware naming, chaining proteasome dysfunction to UPR and PKR-driven
  interferonopathy, and capturing mechanism-grounded treatment evidence for
  baricitinib and anifrolumab.
has_subtypes:
- name: PRAAS1
  display_name: PRAAS1 (PSMB8)
  subtype_term:
    preferred_term: proteasome-associated autoinflammatory syndrome 1
    term:
      id: MONDO:0054698
      label: proteasome-associated autoinflammatory syndrome 1
  genes:
  - preferred_term: PSMB8
    description: >-
      Encodes the inducible immunoproteasome catalytic subunit beta-5i. Recessive
      loss-of-function variants are the founding PRAAS genotype and the one the
      dominant and digenic architectures were recognised against.
    term:
      id: hgnc:9545
      label: PSMB8
  description: >-
    The PSMB8-associated form and the reference presentation of the umbrella
    disease. Recessive variants in the inducible beta-5i catalytic subunit cause
    CANDLE, and the same gene underlies the JMP presentation curated in this
    entry. Per-gene detail is in the PSMB8 record of the genetic section.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:26524591
      reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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)
      explanation: >-
        States the recessive architecture of the PSMB8-associated form directly.
  evidence:
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing."
    explanation: >-
      The discovery study establishes PSMB8 as causative for the JMP presentation,
      one of the historically named phenotypes this subtype row covers.
- name: PRAAS2
  display_name: PRAAS2 (POMP)
  subtype_term:
    preferred_term: proteasome-associated autoinflammatory syndrome 2
    term:
      id: MONDO:0054700
      label: proteasome-associated autoinflammatory syndrome 2
  genes:
  - preferred_term: POMP
    description: >-
      Encodes proteasome maturation protein, a chaperone for proteasome assembly
      that is critical for incorporating the catalytic subunits. The reported
      disease variants are frameshifts in the penultimate exon that escape
      nonsense-mediated decay and act by a dominant-negative mechanism, so this
      is an assembly-chaperone defect rather than a proteasome-subunit defect.
    term:
      id: hgnc:20330
      label: POMP
  description: >-
    The POMP-associated form, distinguished by early-onset combined
    immunodeficiency alongside the inflammatory neutrophilic dermatosis and
    autoimmunity. Its discovery study named it POMP-related autoinflammation and
    immune dysregulation disease (PRAID). PRAAS2 is the name MONDO:0054700 carries
    as a synonym, mapped to OMIM:618048.
  inheritance:
  - name: Autosomal dominant, de novo
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    description: >-
      A single heterozygous POMP variant is sufficient, acting by a
      dominant-negative mechanism on proteasome assembly.
    evidence:
    - reference: PMID:29805043
      reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        de novo heterozygous frameshift variants in the penultimate exon of POMP
        escape nonsense-mediated mRNA decay (NMD) and result in a truncated
        protein that perturbs proteasome assembly by a dominant-negative
        mechanism
      explanation: >-
        Reports both the de novo heterozygous architecture and the
        dominant-negative mechanism that makes one allele sufficient.
    - reference: PMID:26524591
      reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        1 patient was heterozygous for a POMP mutation, thus establishing a
        digenic and autosomal dominant inheritance pattern of PRAAS
      explanation: >-
        Independent report of a single heterozygous POMP variant in a PRAAS
        patient, cited for the dominant arm it establishes.
  evidence:
  - reference: PMID:38111302
    reference_title: Proteasome-associated autoinflammatory syndrome 2 in a neonate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Proteasome-associated autoinflammatory syndrome-2 (PRAAS2) is characterized by early onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity."
    explanation: >-
      Names the PRAAS2 entity and its defining features, which is what this
      subtype row asserts.
  - reference: PMID:38111302
    reference_title: Proteasome-associated autoinflammatory syndrome 2 in a neonate.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel de novo frameshift proteasome maturation protein (POMP) mutation (c.333delT (p.t111fs)) was detected, confirming the diagnosis."
    explanation: >-
      Ties the PRAAS2 diagnosis to a de novo POMP frameshift variant in a
      further, independent patient.
  - reference: PMID:29805043
    reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity."
    explanation: >-
      The discovery study's own naming of the POMP entity, and the clinical
      constellation that distinguishes it inside the PRAAS spectrum.
- name: PRAAS3
  display_name: PRAAS3 (PSMB4)
  subtype_term:
    preferred_term: proteasome-associated autoinflammatory syndrome 3
    term:
      id: MONDO:0054699
      label: proteasome-associated autoinflammatory syndrome 3
  genes:
  - preferred_term: PSMB4
    description: >-
      Encodes the beta-7 subunit of the constitutive 20S proteasome. Beta-7 is a
      structural subunit of the beta-ring, not one of the three catalytic active
      site subunits. PSMB4 is reported both as a biallelic cause and as a
      constitutive-component partner in the digenic architecture this entry
      curates.
    term:
      id: hgnc:9541
      label: PSMB4
  description: >-
    The PSMB4-associated form. PSMB4 was one of four proteasome genes newly
    linked to CANDLE/PRAAS by the additive loss-of-function study, which reported
    it both as a compound-heterozygous cause in one patient and as a constitutive
    subunit participating in digenic genotypes.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:26524591
      reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "One patient was compound heterozygous for PSMB4 mutations"
      explanation: >-
        A compound-heterozygous genotype in a single patient, which is the
        recessive architecture of this form.
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      The study that first associated PSMB4 with the disease, naming the subunit
      it encodes.
- name: PRAAS4
  display_name: PRAAS4 (PSMG2)
  subtype_term:
    preferred_term: proteasome-associated autoinflammatory syndrome 4
    term:
      id: MONDO:0030931
      label: proteasome-associated autoinflammatory syndrome 4
  genes:
  - preferred_term: PSMG2
    description: >-
      Encodes proteasome assembly chaperone 2 (PAC2). Like POMP this is an
      assembly-chaperone defect rather than a proteasome-subunit defect, which is
      why the two are wired to the chaperone node of the pathograph.
    term:
      id: hgnc:24929
      label: PSMG2
  description: >-
    The PSMG2-associated form, reported in a patient with CANDLE features who
    also had autoimmune hemolytic anemia. PSMG2 encodes the PAC2 assembly
    chaperone, making this the second chaperone-defect form alongside PRAAS2.
  evidence:
  - reference: PMID:30664889
    reference_title: "Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE."
    explanation: >-
      Establishes PSMG2 as a cause of the CANDLE presentation curated by this
      entry.
- name: PRAAS5
  display_name: PRAAS5 (PSMB10)
  subtype_term:
    preferred_term: proteasome-associated autoinflammatory syndrome 5
    term:
      id: MONDO:0030924
      label: proteasome-associated autoinflammatory syndrome 5
  genes:
  - preferred_term: PSMB10
    description: >-
      Encodes the inducible immunoproteasome catalytic subunit beta-2i (MECL1),
      the third inducible subunit alongside beta-5i (PSMB8) and beta-1i (PSMB9).
    term:
      id: hgnc:9538
      label: PSMB10
  description: >-
    The PSMB10-associated form. Compound-heterozygous PSMB10 variants were found
    in three unrelated Brazilian patients with a CANDLE/PRAAS phenotype, and the
    variants were shown to block incorporation of the beta-2i subunit into mature
    proteasomes.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
    evidence:
    - reference: PMID:37600812
      reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Four patients were compound heterozygous for novel pathogenic variants in
        the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10
      explanation: >-
        Compound heterozygosity across the reported patients is the recessive
        architecture of this form.
  evidence:
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients were compound heterozygous for novel pathogenic variants in
      the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10
    explanation: >-
      Names PSMB10 as an established CANDLE/PRAAS gene and reports the genotypes
      this row is keyed on.
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
    explanation: >-
      Functional evidence that the reported variants act by impairing subunit
      expression or incorporation, the mechanism this entry models downstream.
- name: PRAAS6
  display_name: PRAAS6 (PSMB9)
  subtype_term:
    preferred_term: proteasome-associated autoinflammatory syndrome 6
    term:
      id: MONDO:0968983
      label: proteasome-associated autoinflammatory syndrome 6
  genes:
  - preferred_term: PSMB9
    description: >-
      Encodes the inducible immunoproteasome catalytic subunit beta-1i. The
      reported disease variant is a recurrent de novo heterozygous missense
      change at glycine 156 that sits on the beta-ring interface.
    term:
      id: hgnc:9546
      label: PSMB9
  description: >-
    The PSMB9-associated form. This row is the most contested in the series. The
    two reported patients carried the same de novo heterozygous PSMB9 G156D
    variant and had pulmonary hypertension and combined immunodeficiency without
    lipoatrophy, and their authors proposed a separate category, PRAAS-ID, rather
    than a PRAAS subtype. MONDO:0968983 instead labels it
    proteasome-associated autoinflammatory syndrome 6, maps it to OMIM:620796 and
    places it directly under this umbrella, which is the nosology this row follows;
    the countervailing argument is recorded here and in the entry notes.
  inheritance:
  - name: Autosomal dominant, de novo
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    evidence:
    - reference: PMID:34819510
      reference_title: "Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report a de novo heterozygous missense variant of the PSMB9
        proteasome subunit gene in two unrelated Japanese infants resulting in
        amino acid substitution of the glycine (G) by aspartic acid (D) at
        position 156 of the encoded protein β1i.
      explanation: >-
        Reports the de novo heterozygous architecture in both patients.
  evidence:
  - reference: PMID:34819510
    reference_title: "Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to PRAAS-like manifestations, these individuals suffer from pulmonary hypertension and immunodeficiency, which are distinct from typical PRAAS symptoms."
    explanation: >-
      Supports PSMB9 variants producing a PRAAS-like disease while naming the two
      features that separate it from the rest of the spectrum.
  - reference: PMID:34819510
    reference_title: "Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We propose the term, proteasome-associated autoinflammatory syndrome with immunodeficiency (PRAAS-ID), to indicate a separate category of autoinflammatory diseases, similar to, but distinct from PRAAS, that describes the patients in this study."
    explanation: >-
      Cited against this row's placement: the reporting authors argue the PSMB9
      entity is a separate category rather than a PRAAS subtype.
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      PSMB9 was first linked to CANDLE/PRAAS in this cohort, which is the basis
      for treating the gene as part of the umbrella spectrum.
inheritance:
- name: Autosomal recessive (classic CANDLE/PRAAS)
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    The founding form of the disease: biallelic PSMB8 variants causing CANDLE.
    This remains the commonest architecture and is the reference point the
    dominant and digenic patterns below were recognized against.
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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)
    explanation: >-
      States the recessive PSMB8 architecture of classic CANDLE explicitly.
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    A single heterozygous POMP variant is sufficient in at least one reported
    patient, establishing a dominant arm alongside the recessive and digenic
    ones.
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      1 patient was heterozygous for a POMP mutation, thus establishing a
      digenic and autosomal dominant inheritance pattern of PRAAS
    explanation: >-
      The same sentence that establishes the digenic pattern names the dominant
      one; both are asserted by the discovery study.
- name: Digenic (inducible plus constitutive subunit)
  inheritance_term:
    preferred_term: Digenic inheritance
    term:
      id: HP:0010984
      label: Digenic inheritance
  description: >-
    A distinct and mechanistically specific two-locus architecture: six patients
    from four families each carried a heterozygous missense variant in an
    INDUCIBLE proteasome subunit together with a variant in a CONSTITUTIVE
    subunit. The two lesions are not interchangeable partners drawn from one
    gene set - they hit the two different proteasome populations, which is the
    sense in which the discovery study titled the mechanism additive loss of
    function. Its functional work showed the mutations converging, by varied
    routes, on proteasome activity; the abstract does not decompose the digenic
    phenotype against either subunit class alone, so no such comparison is
    asserted here. Because the Inheritance class has no genes slot, the genes
    in which that study reported mutations are named: PSMA3, PSMB4, PSMB9,
    PSMB8 and POMP - the inducible subunits among them being PSMB8 and PSMB9
    and the constitutive ones PSMA3 and PSMB4. Note the abstract does not say
    which pairs occurred in which digenic family, so the per-family
    combinations are deliberately not stated. A 2026 report extends the pattern to PSMA6
    (PMID:41205671), which is not curated here because no abstract is available
    to quote.
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      6 patients from 4 families were heterozygous for a missense mutation in 1
      inducible proteasome subunit and a mutation in a constitutive proteasome
      subunit
    explanation: >-
      Reports the two-locus genotype and its recurrence across four independent
      families, which is what distinguishes it from a single-family observation.
      Note the abstract states the subunit CLASSES that pair, not the individual
      genes per family.
  - reference: PMID:38578475
    reference_title: "Proteasome-Associated Syndromes: Updates on Genetics, Clinical Manifestations, Pathogenesis, and Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Proteasome-associated diseases have complex inheritance, including
      monogenic, digenic and oligogenic disorders and can be dominantly or
      recessively inherited.
    explanation: >-
      A 2024 review confirming digenic and oligogenic inheritance as an
      established part of the proteasome-disease spectrum, not a single report.

genetic:
- name: Proteasome subunit and assembly-factor loss-of-function variants
  association: Causative
  notes: >
    PRAAS is genetically heterogeneous and includes recessive, digenic, and de
    novo dominant-negative defects affecting proteasome catalytic subunits and
    proteasome assembly factors. Reported genes across the spectrum include
    PSMB8, PSMB9, PSMB7, PSMA3, POMP, PSMG2, PSMB10, PSMA5, and PSMC5. This
    spectrum-level record is retained for the genes in that list which are not the
    gene of any of the six numbered forms curated as subtype rows: PSMB7, PSMA5 and
    PSMC5. Of the two genes
    reported for the first time in the 2023 case series, the authors judged the
    PSMA5 variant most likely disease-causing and stated that the clinical impact
    of the PSMC5 variant could not be determined, so neither is bound as a gene
    here. The numbered forms and their genes are curated as has_subtypes rows with
    matching per-gene records below.
  evidence:
  - reference: PMID:31827472
    reference_title: "Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively."
    explanation: Review abstract defines the umbrella disease genetically and anchors the core subunit and assembly-factor gene set.
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Variants in two previously not associated proteasome genes, PSMA5 and PSMC5, were found in a patient who also carried the PSMB8 founder mutation, p.T75M."
    explanation: Recent case-series evidence expands the PRAAS gene spectrum beyond the earlier canonical set.
- name: PSMB8
  association: Recurrent causative gene
  relationship_type: CAUSATIVE
  subtype: PRAAS1
  gene_term:
    preferred_term: PSMB8
    term:
      id: hgnc:9545
      label: PSMB8
  notes: >
    PSMB8 encodes the inducible immunoproteasome beta-5i catalytic subunit and
    remains the best-established recurrent PRAAS gene across CANDLE,
    Nakajo-Nishimura, and JMP presentations.
  evidence:
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conclude that mutations in PSMB8 cause JMP syndrome, most probably by affecting MHC class I antigen processing."
    explanation: Discovery study establishes PSMB8 as a causative gene for one of the canonical PRAAS presentations.
  - reference: PMID:31046790
    reference_title: "Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients have biallelic mutations in the PSMB8 gene that encodes the β5i catalytic subunit of the immunoproteasome."
    explanation: Case-report abstract confirms PSMB8 as the recurrent disease gene in CANDLE, another historically named PRAAS phenotype.
- name: PSMA3
  association: Constitutive-subunit partner in the digenic architecture
  relationship_type: COOPERATING
  gene_term:
    preferred_term: PSMA3
    term:
      id: hgnc:9532
      label: PSMA3
  notes: >
    PSMA3 encodes the 20S core alpha-7 subunit. It is not the gene of any of the
    six numbered forms curated as subtype rows, and is reported in digenic
    genotypes paired with a variant in an inducible subunit, which is the two-locus
    architecture recorded in the disease-level inheritance section.
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      First association of PSMA3 with the disease, and the subunit it encodes.
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      6 patients from 4 families were heterozygous for a missense mutation in 1
      inducible proteasome subunit and a mutation in a constitutive proteasome
      subunit
    explanation: >-
      Reports the digenic pairing of a constitutive subunit, the class PSMA3
      belongs to, with an inducible one.
- name: POMP
  association: Assembly-chaperone cause of the PRAAS2 form
  relationship_type: CAUSATIVE
  subtype: PRAAS2
  gene_term:
    preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  notes: >
    POMP encodes proteasome maturation protein, the chaperone that incorporates
    the catalytic subunits into the assembling proteasome. Disease variants are
    frameshifts in the penultimate exon that escape nonsense-mediated decay, so a
    truncated protein is made and acts dominant-negatively; that is why a single
    allele suffices here while the proteasome-subunit forms are recessive.
  evidence:
  - reference: PMID:29805043
    reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we characterize and describe POMP-related autoinflammation and immune dysregulation disease (PRAID) discovered in two unrelated individuals with a unique constellation of early-onset combined immunodeficiency, inflammatory neutrophilic dermatosis, and autoimmunity."
    explanation: >-
      Establishes POMP as the cause of a distinct entity within this spectrum in
      two unrelated individuals.
  - reference: PMID:29805043
    reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      de novo heterozygous frameshift variants in the penultimate exon of POMP
      escape nonsense-mediated mRNA decay (NMD) and result in a truncated
      protein that perturbs proteasome assembly by a dominant-negative
      mechanism
    explanation: >-
      Gives the allelic mechanism recorded in this record's notes.
- name: PSMB4
  association: Structural-subunit cause of the PRAAS3 form and digenic partner
  relationship_type: CAUSATIVE
  subtype: PRAAS3
  gene_term:
    preferred_term: PSMB4
    term:
      id: hgnc:9541
      label: PSMB4
  notes: >
    PSMB4 encodes the beta-7 subunit of the constitutive 20S proteasome, a
    structural subunit of the beta-ring rather than one of the three catalytic
    active site subunits. It was reported both as a compound-heterozygous cause in
    a single patient and as one of the constitutive components that pair with an
    inducible subunit in the digenic genotypes described at disease level.
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient was compound heterozygous for PSMB4 mutations"
    explanation: >-
      The biallelic PSMB4 genotype that defines this form.
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: >-
      First association of PSMB4 with the disease, and the subunit it encodes.
- name: PSMG2
  association: Assembly-chaperone cause of the PRAAS4 form
  relationship_type: CAUSATIVE
  subtype: PRAAS4
  gene_term:
    preferred_term: PSMG2
    term:
      id: hgnc:24929
      label: PSMG2
  notes: >
    PSMG2 encodes proteasome assembly chaperone 2 (PAC2). With POMP it is the
    second assembly-chaperone route into the disease, as distinct from the
    subunit route taken by the PSMB and PSMA genes.
  evidence:
  - reference: PMID:30664889
    reference_title: "Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE."
    explanation: >-
      Establishes PSMG2 as a cause of the CANDLE presentation this entry curates.
- name: PSMB10
  association: Catalytic-subunit cause of the PRAAS5 form
  relationship_type: CAUSATIVE
  subtype: PRAAS5
  gene_term:
    preferred_term: PSMB10
    term:
      id: hgnc:9538
      label: PSMB10
  notes: >
    PSMB10 encodes the inducible immunoproteasome catalytic subunit beta-2i
    (MECL1). Reported variants act by preventing propeptide processing or subunit
    incorporation rather than by abolishing catalytic chemistry.
  evidence:
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four patients were compound heterozygous for novel pathogenic variants in
      the known CANDLE/PRAAS associated genes, PSMB8 and PSMB10
    explanation: >-
      Names PSMB10 among the established disease genes and reports the genotypes.
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
    explanation: >-
      Functional support for the incorporation defect described in these notes.
- name: PSMB9
  association: Catalytic-subunit cause of the PRAAS6 form
  relationship_type: CAUSATIVE
  subtype: PRAAS6
  gene_term:
    preferred_term: PSMB9
    term:
      id: hgnc:9546
      label: PSMB9
  notes: >
    PSMB9 encodes the inducible immunoproteasome catalytic subunit beta-1i. Two
    unrelated infants carried the same de novo heterozygous G156D variant, which
    sits on the beta-ring interface and blocks 20S formation. The reporting
    authors proposed the separate label PRAAS-ID for this presentation; see the
    PRAAS6 subtype row for that argument.
  evidence:
  - reference: PMID:34819510
    reference_title: "Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report a de novo heterozygous missense variant of the PSMB9
      proteasome subunit gene in two unrelated Japanese infants resulting in
      amino acid substitution of the glycine (G) by aspartic acid (D) at
      position 156 of the encoded protein β1i.
    explanation: >-
      The gene, the recurrent variant and the de novo heterozygous architecture.
  - reference: PMID:34819510
    reference_title: "Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Structurally, PSMB9 G156D interferes with the β-ring-βring interaction of the wild type protein that is necessary for 20S proteasome formation."
    explanation: >-
      Gives the structural mechanism by which the variant blocks proteasome
      formation, the node this gene is wired to.
pathophysiology:
- name: Proteasome Subunit Loss of Function
  description: >
    Inherited or de novo loss-of-function defects in subunits of the proteasome
    initiate one of the two genetic routes into the PRAAS cascade. The
    inducible immunoproteasome catalytic subunits beta-5i (PSMB8), beta-1i (PSMB9)
    and beta-2i (PSMB10) and the constitutive components beta-7 (PSMB4) and
    alpha-7 (PSMA3) are the subunits reported in this disease. The reported
    variants act by reducing subunit expression, blocking propeptide processing, or
    preventing incorporation into the mature particle.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: PSMB8
    term:
      id: hgnc:9545
      label: PSMB8
  - preferred_term: PSMA3
    term:
      id: hgnc:9532
      label: PSMA3
  - preferred_term: PSMB9
    term:
      id: hgnc:9546
      label: PSMB9
  - preferred_term: PSMB10
    term:
      id: hgnc:9538
      label: PSMB10
  - preferred_term: PSMB4
    term:
      id: hgnc:9541
      label: PSMB4
  downstream:
  - target: Impaired Proteasome Biogenesis and Activity
  evidence:
  - reference: PMID:31827472
    reference_title: "Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively."
    explanation: Establishes the initiating lesion in PRAAS as loss of proteasome or proteasome-assembly function, and separates the subunit genes from the assembly-factor genes.
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
    explanation: Functional evidence for the allelic mechanisms named in this node's description.
- name: Proteasome Assembly Chaperone Loss of Function
  description: >
    The second genetic route into the cascade. Defects in the chaperones that
    build the proteasome rather than in the proteasome subunits themselves: POMP,
    which incorporates the catalytic subunits into the assembling particle, and
    PSMG2, which encodes the PAC2 assembly chaperone. This arm is separated from
    the proteasome-subunit arm because the lesion is in the assembly machinery and
    not in the particle it assembles.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: POMP
    term:
      id: hgnc:20330
      label: POMP
  - preferred_term: PSMG2
    term:
      id: hgnc:24929
      label: PSMG2
  downstream:
  - target: Impaired Proteasome Biogenesis and Activity
    description: >-
      Loss of chaperone function leaves the catalytic subunits unincorporated, so
      mature proteasome is not formed.
    evidence:
    - reference: PMID:29805043
      reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        de novo heterozygous frameshift variants in the penultimate exon of POMP
        escape nonsense-mediated mRNA decay (NMD) and result in a truncated
        protein that perturbs proteasome assembly by a dominant-negative
        mechanism
      explanation: Reports the chaperone defect perturbing proteasome assembly, which is this edge.
  evidence:
  - reference: PMID:31827472
    reference_title: "Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively."
    explanation: Names POMP and PSMG2 as the assembly-factor causes, which is the gene set bound to this node.
  - reference: PMID:29805043
    reference_title: "Heterozygous Truncating Variants in POMP Escape Nonsense-Mediated Decay and Cause a Unique Immune Dysregulatory Syndrome."
    supports: SUPPORT
    quote_role: BACKGROUND
    evidence_source: OTHER
    snippet: "Proteasome maturation protein (POMP) is a chaperone for proteasome assembly and is critical for the incorporation of catalytic subunits into the proteasome."
    explanation: States the chaperone role that makes POMP loss an assembly defect rather than a catalytic defect.
  - reference: PMID:30664889
    reference_title: "Novel proteasome assembly chaperone mutations in PSMG2/PAC2 cause the autoinflammatory interferonopathy CANDLE/PRAAS4."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in the proteasome chaperone, PSMG2/PAC2 are a novel cause of CANDLE."
    explanation: Supports the second chaperone gene bound to this node as a cause of the disease.
- name: Impaired Proteasome Biogenesis and Activity
  description: >
    PRAAS variants disrupt proteasome subunit expression, assembly, and mature
    proteasome function, reducing proteolytic capacity.
  biological_processes:
  - preferred_term: proteasome-mediated protein degradation
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: DECREASED
  downstream:
  - target: Proteotoxic and Endoplasmic Reticulum Stress
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Function evaluation revealed that these mutations variably affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity."
    explanation: Functional studies show that PRAAS-associated variants impair proteasome assembly and catalytic output.
  - reference: PMID:37600812
    reference_title: "Identification of eight novel proteasome variants in five unrelated cases of proteasome-associated autoinflammatory syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All newly identified mutations substantially impact the steady-state expression of the affected proteasome subunits and/or their incorporation into mature 26S proteasomes."
    explanation: Additional contemporary functional evidence links newly reported PRAAS variants to defective mature proteasome formation.
- name: Proteotoxic and Endoplasmic Reticulum Stress
  description: >
    Impaired proteasome function causes accumulation of ubiquitinated or
    misfolded proteins, engaging stress pathways including the unfolded
    protein response.
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  downstream:
  - target: PKR-Mediated Type I Interferon Signaling
  evidence:
  - reference: PMID:31827472
    reference_title: "Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature."
    explanation: Review abstract directly links proteasome defects to ubiquitinated-protein accumulation and the interferon signature.
  - reference: PMID:31827472
    reference_title: "Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress)."
    explanation: Supports ER stress and UPR engagement as a mechanistic bridge between proteasome dysfunction and interferon activation.
- name: PKR-Mediated Type I Interferon Signaling
  description: >
    Protein kinase R senses proteotoxic stress in PRAAS and amplifies type I
    interferon and inflammatory signaling.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  downstream:
  - target: Persistent Interferon Signature
  evidence:
  - reference: PMID:35148201
    reference_title: "Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress."
    explanation: Mechanistic study identifies PKR as the sensor that connects proteasome dysfunction to inflammatory signaling.
  - reference: PMID:35148201
    reference_title: "Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24)."
    explanation: Abstract-level evidence specifies the proximate signal sensed by PKR during proteasome dysfunction.
- name: Persistent Interferon Signature
  description: >
    Patient immune and stromal cells show a sustained interferon-response
    program that remains a central molecular hallmark across PRAAS genotypes.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  evidence:
  - reference: PMID:26524591
    reference_title: "Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient-isolated hematopoietic and nonhematopoietic cells exhibited a strong IFN gene-expression signature, irrespective of genotype."
    explanation: Demonstrates that the interferon program is a shared downstream phenotype across genetically diverse PRAAS cases.
  - reference: PMID:21953331
    reference_title: "Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Microarray profiles and monocyte STAT-1 activation suggested a unique IFN signaling signature, unlike in other autoinflammatory disorders."
    explanation: Early CANDLE cohort data confirm monocyte interferon-pathway activation as a core disease feature.
  downstream:
  - target: Periodic fever
    causal_link_type: DIRECT
    description: >-
      Recurrent fever driven by the sustained interferon response rather than by an inflammasome cycle — which is what distinguishes this from the classic periodic fever syndromes.
  - target: Chilblains
    causal_link_type: DIRECT
    description: >-
      Acral violaceous lesions, the characteristic cutaneous sign of a type I interferonopathy.
  - target: Panniculitis
    causal_link_type: DIRECT
    description: >-
      Inflammation of subcutaneous fat.
  - target: Lipodystrophy
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Progressive loss of subcutaneous fat, which in this disease follows the panniculitis rather than occurring independently — the sequence is inflammation first, then loss.
  - target: Skeletal muscle atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Progressive muscle wasting, part of the same progressive-loss phenotype.
  - target: Joint contracture
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Contractures developing as the inflammatory and atrophic process crosses joints.
  - target: Microcytic anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Anaemia of chronic inflammation, microcytic here.
phenotypes:
- name: Periodic fever
  category: Systemic
  description: >
    Recurrent febrile inflammatory episodes are a core systemic manifestation
    across the PRAAS spectrum.
  phenotype_term:
    preferred_term: periodic fever
    term:
      id: HP:0032323
      label: Periodic fever
  evidence:
  - reference: PMID:31576159
    reference_title: "Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers."
    explanation: Review abstract identifies periodic fever as a canonical feature of Nakajo-Nishimura syndrome within the PRAAS spectrum.
- name: Chilblains
  category: Dermatologic
  description: >
    Pernio-like acral inflammatory lesions are a characteristic skin finding in
    the PRAAS/Nakajo-Nishimura end of the spectrum.
  phenotype_term:
    preferred_term: pernio-like rash
    term:
      id: HP:0009710
      label: Chilblains
  evidence:
  - reference: PMID:31576159
    reference_title: "Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Phenotypes of NNS patients are periodic fever, pernio-like rash, nodular erythema-like eruptions, and lipomuscular dystrophy, especially in the upper body, leading to the characteristic long, clubbed fingers."
    explanation: The same review abstract supports pernio-like acral skin inflammation as part of the PRAAS phenotype spectrum.
- name: Lipodystrophy
  category: Metabolic
  description: >
    Progressive lipodystrophy is one of the most distinctive shared features
    across CANDLE, NNS, and JMP presentations.
  phenotype_term:
    preferred_term: lipodystrophy
    term:
      id: HP:0009125
      label: Lipodystrophy
  evidence:
  - reference: PMID:31046790
    reference_title: "Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations include presentation in the first year of life, episodes of fever accompanied by erythematous skin lesions, progressive lipodystrophy, violaceous periorbital swelling and failure to thrive."
    explanation: Case-report abstract confirms progressive lipodystrophy as a key CANDLE manifestation within PRAAS.
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
    explanation: Discovery study supports lipodystrophy as a defining feature in the JMP presentation of the PRAAS spectrum.
- name: Panniculitis
  category: Dermatologic
  description: >
    Lobular panniculitis is part of the inflammatory skin and adipose-tissue
    phenotype in PRAAS, especially in JMP/CANDLE presentations.
  phenotype_term:
    preferred_term: panniculitis
    term:
      id: HP:0012490
      label: Panniculitis
  evidence:
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
    explanation: JMP discovery abstract directly supports panniculitis-associated adipose inflammation in PSMB8-related PRAAS.
- name: Joint contracture
  category: Musculoskeletal
  description: >
    Progressive fixed joint limitation is a recurrent disabling musculoskeletal
    manifestation across the PRAAS spectrum.
  phenotype_term:
    preferred_term: joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
    explanation: The JMP discovery abstract directly anchors joint contracture as a core spectrum phenotype.
- name: Skeletal muscle atrophy
  category: Musculoskeletal
  description: >
    Progressive muscular wasting is a recognized phenotype at the
    Nakajo-Nishimura/JMP end of the PRAAS spectrum.
  phenotype_term:
    preferred_term: skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
    explanation: Supports muscle atrophy as a defining feature of a canonical PSMB8-related PRAAS presentation.
- name: Microcytic anemia
  category: Hematologic
  description: >
    Chronic microcytic anemia is part of the systemic inflammatory phenotype in
    the JMP/PRAAS presentation.
  phenotype_term:
    preferred_term: microcytic anemia
    term:
      id: HP:0001935
      label: Microcytic anemia
  evidence:
  - reference: PMID:21129723
    reference_title: "PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed homozygosity mapping in two recently reported pedigrees from Portugal and Mexico with an autosomal-recessive autoinflammatory syndrome characterized by joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP)."
    explanation: Discovery study supports chronic microcytic anemia as a characteristic hematologic feature within PRAAS.
treatments:
- name: Baricitinib therapy
  description: >
    JAK1/2 inhibition with baricitinib can suppress interferon-driven disease
    activity in PRAAS, but dose reductions may precipitate rebound flares.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: baricitinib
      term:
        id: CHEBI:95341
        label: baricitinib
  evidence:
  - reference: PMID:38653530
    reference_title: "Disease flares with baricitinib dose reductions and development of flare criteria in patients with CANDLE/PRAAS."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/proteasome-associated autoinflammatory syndrome (CANDLE/PRAAS) respond to the janus kinase inhibitor 1/2 inhibition with baricitinib at exposures higher than in rheumatoid arthritis."
    explanation: PRAAS-specific cohort data support baricitinib as an effective mechanism-based therapy and show its exposure-response dependence.
  - reference: PMID:31046790
    reference_title: "Disease course and treatment effects of a JAK inhibitor in a patient with CANDLE syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have treated the patient with the JAK inhibitor baricitinib for the past year and we observed a significant amelioration of his inflammatory episodes, skin and joint manifestations, and improvements in physical activities and growth."
    explanation: Independent case evidence supports clinically meaningful baricitinib benefit in CANDLE/PRAAS.
- name: Anifrolumab therapy
  description: >
    IFNAR1 blockade with anifrolumab is an emerging treatment option for type I
    interferonopathies and has early supportive evidence in CANDLE/PRAAS.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anifrolumab
      term:
        id: NCIT:C166658
        label: Anifrolumab
  evidence:
  - reference: PMID:39441221
    reference_title: "Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show in four patients with SAVI and one patient with CANDLE syndrome that blockade of the IFNAR1 receptor (Anifrolumab) exerts an additive effect over JAK-inhibitor alone."
    explanation: The case-series abstract directly includes one CANDLE patient and supports IFNAR1 blockade as a rational add-on strategy.
  - reference: PMID:39441221
    reference_title: "Normalized Interferon Signatures and Clinical Improvements by IFNAR1 Blocking Antibody (Anifrolumab) in Patients with Type I Interferonopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Anifrolumab normalizes IFN-I signature genes and relieves symptoms beyond what is typically achieved by a JAK-inhibitor (Baricitinib) alone in patients with type-I interferonopathies."
    explanation: Supports the specific therapeutic rationale of directly suppressing IFN-I signaling in interferonopathy-spectrum disease.
📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Review: Proteasome-Associated Autoinflammatory Syndrome (Changes required) · 2026-05-31T03:01:54Z · View source

GitHub review issue: https://github.com/monarch-initiative/dismech/issues/3573 Issue state: OPEN Issue created: 2026-05-31T03:01:54Z Issue updated: 2026-05-31T03:01:54Z Issue closed: not closed Review decision: Changes required Labels: review ## Completed curation review - Disease: **Proteasome-Associated Autoinflammatory Syndrome** - Entry: `kb/disorders/Proteasome_Associated_Autoinflammatory_Syndrome.yaml` - Selection basis: #105 of the least-recently edited Mendelian entries - Review decision: **Changes required** - Validation stance: assumes schema, ontology-term, and reference validation pass; this is a biological/clinical/content review. ## Findings 1. Blocking: the entry has no `diagnosis` section. Add disease-specific diagnostic criteria, recommended tests/imaging/biochemical markers, and molecular confirmation strategy for Proteasome-Associated Autoinflammatory Syndrome; this is necessary for curators to evaluate whether the modeled mechanism and phenotype scope match the intended disease. 2. Research-artifact consumption: matching deep-research artifact(s) exist and should be treated as first-class review inputs. Compare the YAML against the artifact(s), especially for central mechanisms, subtype-specific features, treatments/trials, and diagnostic/surveillance details rather than only schema-valid content. 3. Disease-boundary check: no subtypes are modeled. Confirm this is intentionally a single pathomechanism entry and not a spectrum that should expose subtypes, genotype classes, or clinically distinct forms. 4. Pathophysiology review: the main modeled mechanisms include Proteasome Subunit and Assembly-Factor Loss of Function, Impaired Proteasome Biogenesis and Activity, Proteotoxic and Endoplasmic Reticulum Stress, PKR-Mediated Type I Interferon Signaling. Check that each is an atomic event with direct evidence and that downstream edges do not encode multi-step chains or unsupported causal leaps from gene/product defect to organ-level phenotype. 5. Treatment modeling: treatments are present (Baricitinib therapy, Anifrolumab therapy). Check therapeutic agents, subtype applicability, evidence strength, and surveillance/supportive-care needs; avoid broad treatment claims that are not tied to the relevant phenotype or disease stage. 6. Evidence/reference check: top references include PMID:31827472, PMID:37600812, PMID:21129723, PMID:31046790. Spot-check that snippets directly support the specific claim, frequency, and evidence_source classification, especially where the same PMID is reused across phenotype, mechanism, and treatment assertions. ## Content-Completeness Checklist - Phenotype coverage: review major phenotypes such as Periodic fever, Chilblains, Lipodystrophy, Panniculitis, Joint contracture. - Subtype completeness: N/A or not modeled; confirm no required subtype split. - Pathophysiology depth: mechanisms present but require atomicity/evidence review. - Treatments and trials: present; verify standard-vs-investigational scope. - Genetics: genetic section present; verify inheritance, variant classes, and genotype-phenotype claims. - Biomarkers/diagnostics: gap noted; diagnosis absent. - References/research consumption: compare the YAML against listed sources and local research artifacts; do not treat retrieval-heavy papers as issues unless they are disease-specific and directly modelable. ## Suggested Remediation Resolve the blocking diagnostic/baseline gaps first, then tighten subtype-specific claims, pathophysiology atomicity, treatment/trial scope, and evidence-to-claim alignment. Keep deterministic schema/term/reference validation separate from this biological review. ## Sources Used - Local research artifact: `research/Proteasome_Associated_Autoinflammatory_Syndrome-deep-research-asta.md` - PMID:31827472: https://pubmed.ncbi.nlm.nih.gov/31827472/ - PMID:37600812: https://pubmed.ncbi.nlm.nih.gov/37600812/ - PMID:21129723: https://pubmed.ncbi.nlm.nih.gov/21129723/ - PMID:31046790: https://pubmed.ncbi.nlm.nih.gov/31046790/ No YAML files or `references_cache/*.md` files were edited for this review.

Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Proteasome-Associated Autoinflammatory Syndrome. Core disease mechanisms,...
Asta Scientific Corpus Retrieval 20 citations 2026-04-13T22:25:34.312535

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Proteasome-Associated Autoinflammatory Syndrome. Core disease mechanisms,...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Dysfunctional immunoproteasomes in autoinflammatory diseases

  • Authors: H. Arimochi, Yuki Sasaki, A. Kitamura, K. Yasutomo
  • Year: 2016
  • Venue: Inflammation and Regeneration
  • URL: https://www.semanticscholar.org/paper/f8ac8f6a0b7ab08ecd814880c28ff8dfd1395a11
  • DOI: 10.1186/s41232-016-0011-8
  • PMID: 29259686
  • PMCID: 5721717
  • Citations: 9
  • Summary: Analysis of causal gene mutations, assessment of patients’ phenotypic changes, and appropriate animal models will be indispensable for clarifying the underlying mechanisms responsible for the development of autoinflammatory syndromes and establishing curative approaches.
  • Evidence snippets:
  • Snippet 1 (score: 0.579) > Improvements in genotyping efficiency, sequencing technology, and statistical methodology have made it possible for researchers to identify specific gene mutations associated with autoinflammatory syndromes. Some mutations and polymorphisms connected to dysregulated proteasome syndromes have been reported, but the functional consequences of genetic variations are not fully understood. To increase our understanding of the pathophysiology of these diseases, basic and advanced studies with tissues from patients and genetically modified animals will be required to determine how the mutations affect cellular physiology and proteasome function. Analysis of causal gene mutations, the subsequent phenotypic changes in autoinflammatory syndrome patients, and establishment of a proper animal model for these diseases will be indispensable to clarify the mechanisms of autoinflammatory syndrome development and to develop cures for these diseases.

[2] Role of Proteasomes in Inflammation

  • Authors: Carl Christoph Goetzke, F. Ebstein, T. Kallinich
  • Year: 2021
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/38db69eac24c0c546e0d313ab2f3301c6f007124
  • DOI: 10.3390/jcm10081783
  • PMID: 33923887
  • PMCID: 8072576
  • Citations: 71
  • Influential citations: 1
  • Summary: A light is cast on the different clinical aspects of proteasomal activity in human disease and the currently studied therapeutic approaches are summarized.
  • Evidence snippets:
  • Snippet 1 (score: 0.523) > The ubiquitin–proteasome system (UPS) is involved in multiple cellular functions including the regulation of protein homeostasis, major histocompatibility (MHC) class I antigen processing, cell cycle proliferation and signaling. In humans, proteasome loss-of-function mutations result in autoinflammation dominated by a prominent type I interferon (IFN) gene signature. These genomic alterations typically cause the development of proteasome-associated autoinflammatory syndromes (PRAAS) by impairing proteasome activity and perturbing protein homeostasis. However, an abnormal increased proteasomal activity can also be found in other human inflammatory diseases. In this review, we cast a light on the different clinical aspects of proteasomal activity in human disease and summarize the currently studied therapeutic approaches.

[3] Disorders of ubiquitylation: unchained inflammation

  • Authors: D. Beck, Achim Werner, D. Kastner, I. Aksentijevich
  • Year: 2022
  • Venue: Nature Reviews. Rheumatology
  • URL: https://www.semanticscholar.org/paper/f70d358e861f27cf6e94321d108ac07c274b9df4
  • DOI: 10.1038/s41584-022-00778-4
  • PMID: 35523963
  • PMCID: 9075716
  • Citations: 94
  • Summary: The authors describe the molecular pathogenesis of disorders of ubiquitylation that result in innate immune overactivation and systemic autoinflammatory disease and suggest novel treatment avenues.
  • Evidence snippets:
  • Snippet 1 (score: 0.482) > Dysregulation of ubiquitylation is linked to many distinct disorders of recurrent systemic inflammation that are collectively known as systemic autoinflammatory diseases (SAIDs) 26 . Studies of patients with SAIDs and of animal models that phenocopy these conditions have revealed basic mechanisms related to innate immunity that are widely applicable across many different disease states 9 . SAIDs are caused by genetic mutations that lead to enhanced or constitutive inflammation, either gain-of-function mutations in activators or sensors of immune responses (such as NLRP3, mutation of which results in cryopyrin-associated periodic syndrome) 27,28 , or loss-of-function mutations in inflammatory repressors (such as IL1RN, mutation of which results in deficiency of IL-1 receptor antagonist) 29,30 . Identification of the molecular causes of such diseases is important to enable correct clinical diagnosis and selection of targeted therapies. > SAIDs can be categorized according to a number of parameters, such as clinical manifestation 31 , genetics 32 and molecular pathogenesis 33 ; however, in this Review, we focus on the biochemical pathways of ubiquitylation in autoinflammatory diseases as a defining feature. Depending on which step in the ubiquitylation hierarchy is compromised, dysregulation of ubiquitylation can directly affect a particular signalling pathway (for example, through mutations affecting E3 ligases and deubiquitylases) that will ultimately result in activation of cellular stress responses, or it can cause general cellular stress as an immediate consequence (for example, through mutations affecting E1 enzymes or the proteasome). We focus here on existing data from human genetic diseases and supporting evidence from relevant model organisms to review the current understanding of the pathology and molecular basis of associated pheno types. Strikingly, defects in general components of the ubiquitin-proteasome system (UPS) and in highly substrate-specific ubiquitin ligation and deconjugation enzymes can lead to overlapping clinical presentations, suggesting commonalities that are not apparent at the level of known molecular aetiology. Given the highly targetable nature of the ubiquitin pathway 34 , conceptually connecting these diseases may be important for designing rational therapeutics across diagnoses.

[4] Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases

  • Authors: I. Figueras-Nart, J. Mascaró, X. Solanich, J. Hernández-Rodríguez
  • Year: 2019
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/a35ef549aec6f85304e8a71d2e547781e9ae64c7
  • DOI: 10.3389/fimmu.2019.02448
  • PMID: 31736939
  • PMCID: 6828938
  • Citations: 43
  • Influential citations: 1
  • Summary: This review intends to provide clinical and histopathological knowledge about cutaneous involvement in monogenic autoinflammatory diseases with cutaneous expression by using this classification.
  • Evidence snippets:
  • Snippet 1 (score: 0.481) > IFN interacts with its surface receptor IFN-α and induces the STAT pathway, which induces the transcription of IFN genes and promotes antiviral activity. In addition, proteins regulating the synthesis or degradation of nucleic acids such as TREX1, SAMHDI, and RNase H2 play an important role in IFN genes activation. Immunoproteasomes are protein complexes that degrade ubiquitinated intracellular proteins and are implicated in cellular stress responses, as well as activating IFN (11,13). > IL-1-mediated and IFN type I-mediated autoinflammatory diseases and their main genetic and pathogenic aspects are illustrated in Figure 1. > Over time, different classifications of monogenic autoinflammatory diseases have been proposed according to molecular and etiopathogenic mechanisms involved (11,15), type of inheritance (16), genetic background and clinical presentation (17,18). Apart from FMF and CAPS, other wellcharacterized monogenic inflammasomopathies comprise TNF receptor-associated periodic syndrome (TRAPS), hyper-IgD syndrome (HIDS), pediatric granulomatous arthritis (Blau syndrome and early onset sarcoidosis), pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA), deficiency of IL-1 receptor antagonist (DIRA) and deficiency of interkeukin-36 receptor antagonist (DITRA). All the monogenic autoinflammatory diseases covered in this review classified according to the major pathogenic mechanism are listed in Table 1. > Polygenic or multifactorial autoinflammatory diseases are defined as complex systemic disorders sharing an autoinflammatory and sometimes autoimmune background, with an unknown genetic cause.

[5] Protein kinase R is an innate immune sensor of proteotoxic stress via accumulation of cytoplasmic IL-24

  • Authors: Sophia Davidson, Chien-Hsiung Yu, A. Steiner, F. Ebstein, Paul J. Baker et al.
  • Year: 2022
  • Venue: Science Immunology
  • URL: https://www.semanticscholar.org/paper/b6da201d281b7d44682058acacd86909d8bf4747
  • DOI: 10.1126/sciimmunol.abi6763
  • PMID: 35148201
  • Citations: 49
  • Influential citations: 2
  • Summary: Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon and NF-κB signaling and protein kinase R (PKR) is identified as an innate immune sensor for proteotoxic stress, causing inflammation observed in the disease PRAAS.
  • Evidence snippets:
  • Snippet 1 (score: 0.477) > Proteasome dysfunction can lead to autoinflammatory disease associated with elevated type I interferon (IFN-αβ) and NF-κB signaling; however, the innate immune pathway driving this is currently unknown. Here, we identified protein kinase R (PKR) as an innate immune sensor for proteotoxic stress. PKR activation was observed in cellular models of decreased proteasome function and in multiple cell types from patients with proteasome-associated autoinflammatory disease (PRAAS). Furthermore, genetic deletion or small-molecule inhibition of PKR in vitro ameliorated inflammation driven by proteasome deficiency. In vivo, proteasome inhibitor–induced inflammatory gene transcription was blunted in PKR-deficient mice compared with littermate controls. PKR also acted as a rheostat for proteotoxic stress by triggering phosphorylation of eIF2α, which can prevent the translation of new proteins to restore homeostasis. Although traditionally known as a sensor of RNA, under conditions of proteasome dysfunction, PKR sensed the cytoplasmic accumulation of a known interactor, interleukin-24 (IL-24). When misfolded IL-24 egress into the cytosol was blocked by inhibition of the endoplasmic reticulum–associated degradation pathway, PKR activation and subsequent inflammatory signaling were blunted. Cytokines such as IL-24 are normally secreted from cells; therefore, cytoplasmic accumulation of IL-24 represents an internal danger-associated molecular pattern. Thus, we have identified a mechanism by which proteotoxic stress is detected, causing inflammation observed in the disease PRAAS. Description Under conditions of proteasome dysfunction, IL-24 accumulated in the cytosol and triggered PKR-mediated inflammation. Stress leads to IL-24 danger It is unclear how proteasome dysfunction leads to inflammation in patients with proteasome-associated autoinflammatory syndrome (PRAAS). Davidson et al. used multiple knockout cell lines, knockout mice, and primary PRAAS patient samples to identify that protein kinase R (PKR) activation drove elevated innate immune responses. Activation of PKR was induced by the cytoplasmic

[6] Targeted Drugs for Cancer Therapy: Small Molecules and Monoclonal Antibodies

  • Authors: B. Baldo, N. Pham
  • Year: 2020
  • Venue: Drug Allergy
  • URL: https://www.semanticscholar.org/paper/8d0fa01c6728505dbf2d557c8fb21703bdd9d376
  • DOI: 10.1007/978-3-030-51740-3_14
  • PMCID: 7979054
  • Citations: 3
  • Summary: Severe infusion reactions provoked by mAbs can resemble anaphylaxis, cytokine-release syndrome, infusion, and type I allergic reactions, while tumor lysis syndrome, unlike CRS, is easy to distinguish from type I immediate reactions.
  • Evidence snippets:
  • Snippet 1 (score: 0.468) > Fig. 14.7 Diagrammatic representation of the proteasome and its role in protein degradation via the ubiquitinproteasome pathway. After being tagged with ubiquitin and unfolded for degradation on the 19S regulatory particles which aid the opening of a proteolytic gate in the 20S core, proteins are degraded into small peptides in the barrel-shaped core where β1 caspase-, β2 trypsin-, and β5 chymotrypsin-like activities reside. Regulatory particles are composed of a base (dark blue), lid (yellow-brown), and so-called arm (pink). The 20S proteolytic core may be capped at one or both ends by a 19S regulatory particle. > Proteasomes are thus referred to as single-capped (sedimentation coefficient ~26S) or double-capped (~30S). In the literature, the term 26S proteasome is often used incorrectly when referring to the double-capped form. > The double-capped complex is thought to be the functional proteasome unit in the cell a stimulant in attempts to understand the molecular mechanisms underlying its clinical effectiveness and identifying new drugs acting on the same pathway. > Gastrointestinal symptoms, thrombocytopenia, neutropenia, peripheral neuropathy, neuropathic pain, and fatigue are the most common side effects of bortezomib, and adverse cutaneous reactions to the drug are numerous (Table 14.1). Rash (often pruritic) is frequently reported in more than 10% of patients (an incidence of 8-18% has been stated), and pruritus, erythema, urticaria, periorbital edema, and eczema are commonly seen. Bortezomib has been associated with cases of drug-induced Sweet's syndrome-like reactions (Fig. 14.9) or acute febrile neutrophilic dermatosis, a rare variant of this uncommon skin disease characterized by fever, an elevated neutrophil count, and erythematous lesions infiltrated by neutrophils.

[7] Ubiquitin-proteasome system dysregulation in FAM111B-related poikiloderma and phenotypic spectrum expansion: new case reports and long-term follow-up

  • Authors: Virginie Vignard, M. Maillasson, Anne Bigot, S. Küry, T. Besnard et al.
  • Year: 2025
  • Venue: eBioMedicine
  • URL: https://www.semanticscholar.org/paper/772c41073c92ba0c7664b3d7603425930c0ccc93
  • DOI: 10.1016/j.ebiom.2025.105864
  • PMID: 40840166
  • PMCID: 12396287
  • Summary: A dysfunctional UPS is highlighted as a potential central driver of POIKTMP's molecular pathogenesis, presenting promising therapeutic avenues, and Notably, variants clustering within the D-box domain of FAM111B protein tend to present a more severe phenotype.
  • Evidence snippets:
  • Snippet 1 (score: 0.463) > Our work expanded the cellular phenotype of POIKTMP by introducing protein homoeostasis disruption to its repertoire. In addition, FAM111B variants were associated with the acquisition of specific type I IFN gene (Fig. 10 and Supplementary Fig. S7) and proteomic (Table 2) signatures in POIKTMP cells, a well-known autoinflammatory feature of disorders caused by protein homoeostasis perturbations. 47,48,66 lthough we do not fully understand the biological relevance of these responses in this context, the fact that IFN induces immunoproteasomes and proteasome activators [67][68][69] suggested that they may be part of a compensatory mechanism to enhance proteasome function. > Most importantly, our data indicated that the cellular phenotype of POIKTMP shared features with neurological disorders involving protein homoeostasis perturbations. These disorders notably include late-onset neurodegenerative disorders such as Parkinson disease and Alzheimer disease, 70,71 as well as the more recently described early-onset neurodevelopmental proteasomopathies caused by loss-of-function variants in proteasomal genes. 47,72,73 This concept might initially pique curiosity, especially when considering that POIKTMP patients typically do not exhibit neurological manifestations. 30 However, this contrast can be explained by the low expression of FAM111B in the brain compared to higher expression in other organs such as the skin, pancreas, and gastrointestinal tract. 74 One should emphasize that disruptions in protein homoeostasis are also a hallmark of specific autoinflammatory disorders, particularly chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CAN-DLE), also known as proteasome-associated autoinflammatory syndromes [PRAAS]. 6][77] This raises the question of whether therapeutic approaches used for CANDLE/PRAAS, such as JAK inhibitors for managing dermatological symptoms, 78 could potentially be extended to POIKTMP.

[8] Contribution of the Unfolded Protein Response (UPR) to the Pathogenesis of Proteasome-Associated Autoinflammatory Syndromes (PRAAS)

  • Authors: F. Ebstein, María Cecilia Poli Harlowe, Maja Studencka-Turski, E. Krüger
  • Year: 2019
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/8cacb0ea1cb1fd2761e742520c656faebf95e24b
  • DOI: 10.3389/fimmu.2019.02756
  • PMID: 31827472
  • PMCID: 6890838
  • Citations: 72
  • Summary: The possible role of the UPR in the pathogenesis of PRAAS is discussed and pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition are focused on.
  • Evidence snippets:
  • Snippet 1 (score: 0.461) > Type I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated autoinflammatory syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and-effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role of the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.

[9] Type I Interferonopathies in Children: An Overview

  • Authors: D. M. d’Angelo, Paola Di Filippo, L. Breda, F. Chiarelli
  • Year: 2021
  • Venue: Frontiers in Pediatrics
  • URL: https://www.semanticscholar.org/paper/5931ebb81ed9144967b1546fc3ccfec35582479e
  • DOI: 10.3389/fped.2021.631329
  • PMID: 33869112
  • PMCID: 8044321
  • Citations: 66
  • Influential citations: 3
  • Summary: The characterization of interferonopathy molecular pathogenetic mechanisms is allowing important steps forward in other immune dysregulation diseases, such as systemic lupus erythematosus and inflammatory myositis, implementing the opportunity of a more effective target therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.456) > PRAAS are a heterogeneous group of interferonopathies caused by inherited loss-of-function mutations in genes encoding proteasome subunits of 20S core particles such as PSMB8, PSMB9, PSMB7, and PSMA3 or proteasome chaperone factors such as POMP and PSMG2 (Table 1). These mutations lead to a failure of proteasome complex formation, causing an alteration of intracellular protein homeostasis and the accumulation of ubiquitinated proteins (2,(89)(90)(91)(92). The underlying molecular mechanisms that link this alteration to the activation of the IFN pathway are not yet fully understood. Recently, new insights came from the unfolded protein response (UPR), which originated in response to an accumulation of misfolded proteins in the ER (ER stress). Indeed, defective proteasome compromises the ER-associated protein degradation, resulting in an accumulation of misfolded ER proteins in the lumen. This alteration is determined by three intra ER membrane-resident proteins, in particular the inositol-requiring enzyme 1α/β (IRE1), with subsequent activation of a signal pathway that allows NF-κB activation and IRF3 factor transcription, leading to a IFNdepending inflammation (92,93). PRAAS include the Japanese autoinflammatory syndrome with lipodystrophy (JASL) and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE) syndromes (2). Common clinical features are the presence of pernio-like purplish nodular lesions (neutrophilic dermatosis), panniculitis with progressive lipodystrophy and muscle atrophy, and joint contractures with extremity deformity. Hepatosplenomegaly and hypochromic or hemolytic anemia were also reported. An early metabolic syndrome, with systemic hypertension and dyslipidemia, occurs in 40-80% of patients (89)(90)(91)(92). Proteasome defects were also associated with neurologic diseases.

[10] Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

  • Authors: M. Di Rosa, C. Giallongo, A. Romano, D. Tibullo, G. Li Volti et al.
  • Year: 2020
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/708b84a11830fc7dfc63b28cebc5b6fc5dd8861b
  • DOI: 10.3390/ijms21082926
  • PMID: 32331228
  • PMCID: 7216198
  • Citations: 11
  • Summary: The results demonstrate that IPs and IFNG pathways could be involved in PMF disease and in particular in patients carrying the JAK2V617F mutation.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > Clinical benefits of RUX are partially derived from the reduction of inflammatory cytokines, with an early relief of clinical symptoms and reduction of spleen size after 4 weeks post-treatment [12,13]. Only in a few cases the drug reverts bone marrow fibrosis or reduces the allele burden [14], suggesting that other intracellular signaling in the neoplastic clone or in the host-tumor interaction can affect the clinical course of PMF. > Several papers have shown evidence of a dysregulation of the immune system in the MPNs. PMF is considered as an inflammatory disease where the higher cytokine secretion creates a pro-inflammatory milieu influencing the immune system [15]. It has been demonstrated that several immune defects are principally associated with the presence/absence of the JAK2 V617F mutation [16,17]. Overall, these anomalies could contribute to the development of an immune deficiency state with the potential to promote immune evasion, cancer progression and increased susceptibility to infections [18]. Furthermore, a better understanding of immune biology in the context of PMF would be important for the design of new therapies for PMF. > In eukaryotic cells, the proteasomes (c-20S) are ubiquitously-expressed cellular proteases involved in the degradation of intracellular oxidized proteins following an oxidative insult, through an ATP-independent mechanism [19]. Being ubiquitously expressed, these proteins represent a potential pharmacological target even though with several limitations [20]. To this regard, Bortezomib, a potent and clinically relevant proteasome inhibitor, is intermittently used for multiple myeloma treatment (MM) [21,22] and other inflammatory disease [23][24][25], in order to limit toxic effects [26]. In cells of hematopoietic origins, the classical proteasome is replaced by a different proteasome with an immunological role called immunoproteasome (IPs) [27].

[11] Amyopathic dermatomyositis may be on the spectrum of autoinflammatory disease: A clinical review

  • Authors: Saika Sharmeen, L. Christopher‐Stine, Joann N. Salvemini, P. Gorevic, R. Clark et al.
  • Year: 2024
  • Venue: Rheumatology and Immunology Research
  • URL: https://www.semanticscholar.org/paper/996899888fef5b2dd60f264bb0a1d25a784c1ce7
  • DOI: 10.1515/rir-2024-0005
  • PMID: 38571935
  • PMCID: 10985708
  • Citations: 1
  • Summary: Accumulating data supports a major role of the innate immune system and a similar cytokine profile in SAID patients and may offer therapeutic benefit using interleukin-1 (IL-1) inhibitors.
  • Evidence snippets:
  • Snippet 1 (score: 0.448) > We believe that further genetic profiling will be useful in the context of an autoinflammatory disease gene panel to cover both high and low penetrance variants.This may be necessary to identify genetic variants associated with SAIDs in a subgroup of DM or ADM patients. > The central hypothesis of mechanisms underlying SAIDs is abnormal innate immune response.Mechanisms in SAIDs are complex and heterogenous, depending on individual disease categories.For example, for hereditary recurrent fever syndromes and NOD-like receptor (NLR) associated SAIDs (FMF, CAPS, NLRP12-AID), genetic variations, inflammasomes and aberrant cytokines such as IL-1β, IL-8 and IL-18 contribute to these diseases. [3]NOD2-associated diseases, such as Crohn's disease, Blau syndrome and YAOS are associated with NOD2 mutations that result in abnormal NOD2 activation of RIP2, NF-κB, MAPK, Caspase-1 pathways, as well as cytokine production like IL-1, IL-8 and IL-6. [38]everal new complex clinical autoinflammatory syndromes include systemic inflammation, panniculitis, and myositis due to proteasome defects (PRAAS/CANDLE), vasculopathy, vasculitis, and interstitial lung disease with STING hyperactivity (SAVI), and subacute encephalomyelitis with cerebral calcifications and white matter disease due to cytosolic nucleotide dysregulation (AGS).These diseases are caused by mutations leading to chronic type I interferon (IFN) production as inflammatory mediators that cause autoinflammatory phenotypes. [39]terestingly, there are reports to link inflammasome with DM.

[12] Protein Homeostasis, Aging and Alzheimer’s Disease

  • Authors: T. Morawe, C. Hiebel, Andreas Kern, C. Behl
  • Year: 2012
  • Venue: Molecular Neurobiology
  • URL: https://www.semanticscholar.org/paper/3d06e94f0749ebce0384b7e17a16a242edd60392
  • DOI: 10.1007/s12035-012-8246-0
  • Summary: Since aging is accompanied by changes in cellular protein homeostasis and an increasing demand for protein degradation, aspects of protein folding, misfolding, refolding and, importantly, protein degradation need to be linked to AD pathogenesis.
  • Evidence snippets:
  • Snippet 1 (score: 0.445) > There is quite some evidence that in AD, the proteostasis network is impaired. Based on pathological analysis, AD mouse models, in vitro and cellular investigations a molecular link between chaperones, the ubiquitin-proteasome system, autophagy pathways and pathogenetic mechanisms of AD can be suggested. Deregulation and changes of chaperones and proteasome activity might have serious implications for aging as well as for age-associated diseases. Autophagy pathways are key mechanisms and of vital importance for cellular function and, especially, for cell survival under adverse conditions. Consequently, an effect of proteostasis control on neurodegeneration or, vice versa, of neurodegeneration on proteostasis is reasonable. As with other pathomechanisms that are investigated in the search for the cause of AD, it is still open whether an impairment of proteostasis is an upstream or downstream event during AD onset and progression. Experimental approaches employing mouse models clearly demonstrate that stabilization or induction of proteostasis can be neuroprotective. Whether this can be translated into the human condition and, most importantly, whether supporting proteome integrity can be a real target for pharmacological intervention for the prevention and treatment of AD is currently still open. Also, one has to consider that, e.g. the stimulation of general autophagy may in the long term lead to the stimulation of proliferation of non-neuronal cells, eventually resulting in tumor formation. Indeed, a permanent autophagy induction is known as one cellular mechanism that promotes the escape of cells from proliferation control. As beneficial it may be to support autophagy in post-mitotic neurons that are confronted with disturbed proteostasis and an impairment of proteasome function, this stimulation should target specific autophagy pathways, such as selective chaperone-mediated macroautophagy involved in the degradation of disease-associated protein aggregation. Although there are obviously still many questions to be answered to understand the role of proteostasis in AD (and also in other age-associated neurodegenerative disorders), it is a big step forward in AD research to consider a possible role of pathogenetic pathways that are not directly linked to the usual suspects Aβ and Tau.

[13] Pathogenesis of Inflammation in Skin Disease: From Molecular Mechanisms to Pathology

  • Authors: Simona N Shirley, Abigail E. Watson, Nabiha Yusuf
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a1e66ada3d9b0a74379022fc47ec053e5fe1503b
  • DOI: 10.3390/ijms251810152
  • PMID: 39337637
  • PMCID: 11431851
  • Citations: 37
  • Summary: Several skin diseases such as psoriasis, atopic dermatitis, hidradenitis suppurativa, and scleroderma were described in the paper to demonstrate the widespread influence of inflammation in skin disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.445) > Deep within the core of all anatomic and clinical pathology, cellular components and their complex interactions form the basis of disease. Thus, the secret code to understanding and managing skin disease lies in the land of submicroscopic changes and the miniscule, yet majorly important mechanisms of the body's molecules. Molecular pathology, or the study of disease through the examination of intracellular and extracellular constituents such as proteins and nucleic acids, underpins much of current knowledge regarding the causes of skin disease and the effective targets for therapeutic strategies. Every day, the scientific community's appreciation for molecular sources of skin disease expands as new studies emerge. This literature review, which examines the inflammatory mechanisms of skin disease at a molecular level, seeks to highlight current areas of interest in the field and exciting new advancements in the community's understanding of dermatopathology. After introducing each relevant component of pathogenic inflammation and identifying the specific mechanisms most widely addressed in the recent literature, the details of each process as they apply to individual skin diseases will be discussed. Whether they are classified as autoimmune, autoinflammatory, or both autoimmune and autoinflammatory, all disease processes included in the review involve pathogenic inflammatory mechanisms in the skin. Importantly, all included diseases also represent potential candidates for the emerging avenues of anti-inflammatory therapies mentioned in the review.

[14] Induced pluripotent stem cells representing Nakajo-Nishimura syndrome

  • Authors: N. Kanazawa, Fumiko Honda-Ozaki, M. Saito
  • Year: 2019
  • Venue: Inflammation and Regeneration
  • URL: https://www.semanticscholar.org/paper/807e8addb520e998f152fb2aedfdb67b67361611
  • DOI: 10.1186/s41232-019-0099-8
  • PMID: 31143302
  • PMCID: 6532143
  • Citations: 5
  • Summary: The results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakajo-Nishimura syndrome and related proteasome-associated autoinflammatory syndromes.
  • Evidence snippets:
  • Snippet 1 (score: 0.443) > Nakajo-Nishimura syndrome is a proteasome-associated autoinflammatory syndrome with a distinct homozygous mutation in the PSMB8 gene encoding an inducible β5i subunit of the immunoproteasome. Although it is considered that immunoproteasome dysfunction causes cellular stress and contributes to the production of inflammatory cytokines and chemokines, its detailed mechanism is still unknown. On the other hand, hereditary autoinflammatory diseases are considered as a good target for the analyses using induced pluripotent stem cells, whose differentiation systems to the innate immune cells such as neutrophils and monocytes have been established. Therefore, to elucidate the pathogenesis of Nakajo-Nishimura syndrome, we attempted in vitro disease modeling using patient-derived induced pluripotent stem cells. For analyses, isogenic control cells in which the responsible mutation was repaired and another pair of healthy embryonic stem cells and isogenic mutant cells in which the same mutation was introduced had also been prepared with genetic engineering. By comparing a pair of isogenic cells with the wild-type and the mutant PSMB8 gene after differentiation into monocytes and immortalization to synchronize their differentiation stages, the reduction of immunoproteasome enzyme activity and increased cytokine and chemokine production in the mutant cells without stimulation or with interferon-γ plus tumor necrosis factor-α stimulation were observed, and therefore, the autoinflammatory phenotype was successfully reproduced. Decreased cytokine production was observed by the addition of antioxidants as well as inhibitors for Janus kinase and p38-mitogen-activated protein kinase. At the same time, the increased production of reactive oxygen species and phosphorylation of both signal transducers and activator of transcription 1 and p38-mitogen-activated protein kinase were detected without stimulation. Notably, an antioxidant specifically decreased the constitutive phosphorylation of signal transducers and activator of transcription 1. These results indicate the usefulness of a disease modeling using pluripotent stem cell-derived cells in clarification of the pathomechanism and discovery of new therapeutic drugs for Nakaj

[15] Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease

  • Authors: F. Caso, P. Galozzi, L. Costa, P. Sfriso, L. Cantarini et al.
  • Year: 2015
  • Venue: RMD Open
  • URL: https://www.semanticscholar.org/paper/a04ee83fc3b9dbf5ade58ddb8c35a2c5e1a63479
  • DOI: 10.1136/rmdopen-2015-000097
  • PMID: 26509073
  • PMCID: 4612691
  • Citations: 136
  • Influential citations: 3
  • Summary: Genetic and clinical aspects of Blau syndrome and early-onset sarcoidosis are described, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.
  • Evidence snippets:
  • Snippet 1 (score: 0.442) > In past years, the recognition of different mutations in genes involved in the regulation of inflammatory and apoptotic cellular mechanisms has allowed the characterisation of monogenic autoinflammatory syndromes. 1 Despite their genetic and clinical heterogeneity, the common starting mechanism of these diseases has been identified in the dysfunction of innate immunity and inflammasome processes. 1 Physiologically, the inflammasome represents a multiprotein cytoplasmatic platform that, when assembled, following a proinflammatory trigger, activates caspases, which convert prointerleukin (IL)-1β into its active form, IL-1β, a key molecule of inflammation and innate immunity. 2 In monogenic autoinflammatory syndromes, a genetic-driven erroneous assembly of the inflammasome leads mainly to an overstated increase in IL-1β with an aberrant inflammatory response. 2 Recurrence of the inflammatory attacks are the main temporal characteristics of these diseases, thus reflecting their spontaneous and unbalanced nature. 1 2 Although the knowledge of IL-1β and inflammasome mechanisms represents Key messages ▸ Blau syndrome (BS) and early-onset sarcoidosis (EOS) caused by mutations in the CARD15/ NOD2 gene, represent familial and sporadic phenotypes of the same non-caseating granulomatous inflammatory disease. ▸ The CARD15/NOD2 gene has also been identified as one of the genes linked to susceptibility to Crohn's disease (CD). ▸ Other substitutions in the CARD15/NOD2 gene have also been found in a recently described disorder, called NOD2-associated autoinflammatory disease (NAID). ▸ The improvement of knowledge in molecular mechanisms and diagnosis of these diseases can represent an important breakthrough for improving their outcomes. > the major conceptual progress in the autoinflammatory processes, the recognition of various genetic backgrounds has been useful to classify different groups of autoinflammatory disorders. 1 Among these diseases, two rare non-caseating granulomatosis, Blau syndrome (BS) and early-onset sarcoidosis (EOS), caused by sequence variants in CARD15/NOD

[16] The classification, genetic diagnosis and modelling of monogenic autoinflammatory disorders

  • Authors: F. Moghaddas, S. Masters
  • Year: 2018
  • Venue: Clinical Science (London, England : 1979)
  • URL: https://www.semanticscholar.org/paper/eaeea6f5f6c692b8ba8eb598f992134544b1f611
  • DOI: 10.1042/CS20171498
  • PMID: 30185613
  • PMCID: 6123071
  • Citations: 23
  • Influential citations: 1
  • Summary: This review outlines the classification strategies that have been employed for monogenic autoinflammatory disorders to date, including the primary innate immune pathway or the dominant cytokine implicated in disease pathogenesis, and highlights some of the advantages of these models.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > tokine profile, but little is known about the steps that lead to this alteration. Proteasome-associated autoinflammatory syndrome (PRAAS) is an autosomal recessive autoinflammatory disorder that encompasses conditions previously considered distinct entities: Nakajo-Nishimura syndrome (NKJO), joint contractures, muscular atrophy, microcytic anaemia, and panniculitis-induced lipodystrophy syndrome (JMPS), as well as chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Three publications identified mutations in PSMB8, the β5i catalytic component of the immunoproteasome, as the cause of disease [55][56][57]. Individuals with homozygous loss of function mutations in PSMB8 experienced spontaneous febrile episodes with features of muscle weakness, lipodystrophy as well as neutrophilic and lymphocytic infiltrative skin nodules and evidence of cerebral calcification [55][56][57]. Homozygous mutations were associated with poor proteasome assembly as well as reduced chymotrypsin-like activity and accumulation of ubiquitinated proteins in either Epstein-Barr virus (EBV)-transformed B cells or immortalised lymphoblastoid cell lines from cases [55][56][57]. In these early papers, increased serum IL-6 was noted in all cases, but the role of IFN was only identified later [58]. Liu et al. noted an almost 80-fold increase in IFN-γ-inducible protein 10 (IP-10) in cases compared with healthy controls and individuals with CAPS, prompting whole blood microarray analysis to determine the gene signature of these cases. The IFN pathway was the most differentially regulated pathway in individuals with PRAAS, further supported by stronger STAT1 phosphorylation in response to IFN-γ stimulation of monocytes when compared with healthy controls. These authors also highlighted cases with the clinical phenotype of PRAAS without PSMB8 mutations, later explored by Goldbach-Mansky et al. [59].

[17] Ventilator-induced diaphragmatic dysfunction: pathophysiology, monitoring and advances in potential treatment and prevention

  • Authors: Wei Fu, L. Guan, Qi Liu, Zhefan Xie, Junting You et al.
  • Year: 2025
  • Venue: European Respiratory Review
  • URL: https://www.semanticscholar.org/paper/5c42bb3cd0f8f598a75e0484ea389ece3aeeab49
  • DOI: 10.1183/16000617.0069-2025
  • PMID: 41062169
  • PMCID: 12505153
  • Citations: 5
  • Summary: The epidemiology and pathophysiological mechanisms of VIDD and advances in potential treatment and prevention are summarised.
  • Evidence snippets:
  • Snippet 1 (score: 0.431) > Mechanical ventilation is a life-saving method for those critically ill patients with acute or chronic respiratory failure without assistance. However, even short-term mechanical ventilation can lead to alterations in the fibrous structure and reduced contraction force of the diaphragm, which is defined as ventilator-induced diaphragmatic dysfunction (VIDD). This condition is associated with various risks of adverse clinical outcomes. Research on mechanical ventilation-related respiratory mechanics helps us to understand the macroscopic myotrauma mechanisms of VIDD. Ongoing clinical trials into comprehensive management strategies for lung- and diaphragm-protective ventilation are continually refining respiratory therapy protocols in clinical practice. Although the cellular and molecular mechanisms are not fully defined, pathways involving mitochondrial oxidative stress have been identified as key contributors to disease progression, leading to both accelerated proteolysis and depressed protein synthesis. Additionally, research on the ubiquitin–proteasome pathway, lysosomal autophagy, calpain, caspase-3 and dysfunction of the ryanodine receptor-1 pathway is enhancing our understanding of the downstream mechanisms involved. Promising interventions based on these findings have yielded hopeful results in animal models for preventing VIDD. This review summarises the epidemiology and pathophysiological mechanisms of VIDD and advances in potential treatment and prevention. Shareable abstract Mitochondrial oxidative stress is a key contributor to VIDD. Inhibition of protein synthesis and enhanced degradation are important mechanisms for VIDD. Drugs and optimised mechanical ventilation continue to advance the goal of diaphragm protection. https://bit.ly/3IcJtri

[18] Editorial: Autoinflammatory Diseases: From Genes to Bedside

  • Authors: I. Aksentijevich, A. Soriano, J. Hernández-Rodríguez
  • Year: 2020
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/9fbb99451e1a052657812382bbf20617ae9c74d4
  • DOI: 10.3389/fimmu.2020.01177
  • PMID: 32636839
  • PMCID: 7318105
  • Citations: 9
  • Summary: This poster presents a poster presented at the 2016 International Conference of the American Academy of Pathologists on Autoinflammatory Diseases and Vasculitis to highlight the need to understand more fully the mechanism behind inflammation and its role in disease progression.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Witnessing these developments has been incredibly rewarding for those of us in the field and it will be exciting to see where it goes from here. > In the present issue of Frontiers in Immunology, "Autoinflammatory diseases: from genes to bedside, " the first monographic issue about autoinflammatory diseases, several investigators have contributed with original and review articles covering genetic, pathogenic, epigenetic, clinical and therapeutic aspects of different autoinflammatory conditions. > The "genes" part of the topic explores relevant genetic, pathogenic and epigenetic mechanisms implicated in autoinflammatory diseases. Martorana et al.. review the most common mutations and the evidences of genotype/phenotype correlations of the main monogenic autoinflammatory diseases. The role of NLRP3 and pyrin inflammasomes in the pathogenesis of CAPS, and FMF and pyrin-associated autoinflammation with neutrophilic dermatosis (PAAND), respectively, has been addressed by de Torre-Minguela et al.. Aksentijevich and Zhou describe the latest advances on the pathogenic mechanisms of ubiquitinopathies, a new category of autoinflammatory diseases involved in the NF-κB pathway, which include linear ubiquitin chain assembly complex (LUBAC) and OTULIN deficiencies, and haploinsufficiency of A20. Carta et al.. propose two different pathways of inducing abnormal IL-1β production in autoinflammatory diseases depending on the cell type affected, in which the authors postulate that professional inflammatory cells would cause a direct inflammatory response and non-immune cells may participate indirectly in the inflammatory cascade by releasing stress signals that trigger and propagate inflammation. In the same sense, Gül reviews the concept of autoinflammation and uses it for monogenic and polygenic autoinflammatory diseases associated with seemingly unprovoked inflammatory episodes mediated mainly by the innate immune system. In addition, Gül also proposes and expands nomenclature by using the concept of "hyperinflammatory" state for those disorders characterized by episodes of exaggerated inflammatory response only when triggered by certain factors or situations.

[19] Trained Immunity Contribution to Autoimmune and Inflammatory Disorders

  • Authors: S. C. Funes, M. Ríos, Ayleen Fernández-Fierro, M. S. Di Genaro, A. Kalergis
  • Year: 2022
  • Venue: Frontiers in Immunology
  • URL: https://www.semanticscholar.org/paper/219297438808f2c483bdf5aea5c2e2f35ea096cf
  • DOI: 10.3389/fimmu.2022.868343
  • PMID: 35464438
  • PMCID: 9028757
  • Citations: 41
  • Summary: The metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma are described, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > A critical pathogenetic mechanism in AIF diseases is the dysregulation of the inflammasomes, multiprotein cytoplasmic complexes relevant to innate immunity and inflammatory responses. The main components of inflammasomes are members of the NLR family that detect PAMPs or DAMPs and initiate inflammasome assembly. Thus is induced the proteolytic activation of caspase 1 or 11 and the cleavage and subsequent release of bioactive IL-1b, a key molecule of inflammation and innate immunity (115). Notably, mutations of genes encoding for the components of the proteins involved in the inflammasome (NLRP3) are implicated in the AIF called Cryopyrin-associated periodic syndromes (CAPS) (116). > On the other hand, some AIF diseases are caused by abnormalities of the ubiquitin-proteasome system (UPS), which regulates multiple cellular processes (117). Mutations that cause loss of UPS function in humans lead to a typical type I IFN gene signature and proteasome-associated autoinflammatory syndromes (PRAASs) (118). Although the causes of the induction of sterile inflammation in subjects with PRAAS are still unknown, it is believed that it could be associated with the propagation of endoplasmic reticulum (ER) stress (119). Proteasome defects are known to lead to the retention of misfolded proteins in the ER, leading to inflammation in a pathogen-free setting (120). Another recently described AIF disease related to UPS malfunction is VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (121). Myeloid lineage-restricted somatic mutations of UBA1 (a gene encoding the ubiquitin-activating enzyme 1) characterize VEXAS, leading to inflammation (121). Although the impact of trained immunity in these conditions is unknown to date, it could be assumed that stimuli that establish the capacity of a strengthened response by the innate system could be harmful in these systemic inflammatory diseases.

[20] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

  • Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
  • Year: 2026
  • Venue: Nucleus
  • URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
  • DOI: 10.1080/19491034.2025.2611484
  • PMID: 41489464
  • PMCID: 12773485
  • Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
  • Evidence snippets:
  • Snippet 1 (score: 0.416) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.