Proteosome-associated autoinflammatory syndrome

Summary

Proteosome-associated autoinflammatory syndrome (MONDO:0009726) is a disease (an umbrella term covering 6 Mondo subtypes) caused by PSMB8 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include baricitinib.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PSMB8 (GenCC Strong)
• Umbrella term: 6 Mondo subtypes
• Cohort genes: 1
• ClinVar variants: 179
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	proteosome-associated autoinflammatory syndrome
Mondo ID	MONDO:0009726
MeSH	C538334
OMIM	256040
Orphanet	324977, 2615, 324999, 325004
DOID	DOID:0050553, DOID:0060913
SNOMED CT	702449004
UMLS	C1850568
MedGen	376827
GARD	0013824
Is cancer (heuristic)	no

Also known as: ALDD · ALDD syndrome · amyotrophy fat tissue anomaly · autoinflammation, lipodystrophy, and dermatosis syndrome · autoinflammation-lipodystrophy-dermatosis syndrome · CANDLE syndrome · chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature · chronic atypical neutrophilic dermatosis-lipodystrophy-elevated temperature syndrome · JMP syndrome · Joint contractures - muscle atrophy - microcytic anaemia - panniculitis-induced lipodystrophy · Joint contractures - muscle atrophy - microcytic anemia - panniculitis-induced lipodystrophy · Joint contractures-muscular atrophy-microcytic anemia-panniculitis-associated lipodystrophy syndrome · Nakajo Nishimura syndrome · Nakajo syndrome · Nakajo-Nishimura syndrome · NNS · nodular erythema digital changes · PRAAS · proteasome disability syndrome · proteasome-associated autoinflammatory syndrome (+1 more)

Data availability: 179 ClinVar variants · 2 GenCC gene-disease records · 3 cell lines.

Disease family

An umbrella term covering 6 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › immune system disorder › proteosome-associated autoinflammatory syndrome

Related subtypes (46): hypersensitivity reaction disease, immune system cancer, immune system organ benign neoplasm, bone marrow disorder, thymus gland disorder, inborn error of immunity, leukocyte disorder, psoriasis, spondyloarthropathy, aggressive insulitis, benign insulitis, inflammatory bowel disease, autoimmune disease, TNF receptor 1-associated periodic fever syndrome, epidermodysplasia verruciformis, Vici syndrome, hyperimmunoglobulinemia D with periodic fever, transcobalamin II deficiency, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, granulomatosis with polyangiitis, autosomal recessive osteopetrosis 7, graft versus host disease, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, Roifman syndrome, cryopyrin-associated periodic syndrome, anti-HLA hyperimmunization, acquired immunodeficiency, erythroderma desquamativum, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, familial Mediterranean fever, 22q11.2 deletion syndrome, T-cell large granular lymphocyte leukemia, twin to twin transfusion syndrome, immunodeficiency disease, immunoproliferative disorder, cytokine receptor deficiency, immunodeficiency-related disorder, phagocytic cell dysfunction, thrombocytopenic purpura, lymphoid system disorder, immune reconstitution inflammatory syndrome, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, cytokine release syndrome, early-onset autoimmunity-autoinflammation-immunodeficiency syndrome, CADINS disease, autoinflammation, panniculitis, and dermatosis syndrome

Subtypes (6): proteasome-associated autoinflammatory syndrome 5, proteasome-associated autoinflammatory syndrome 4, proteasome-associated autoinflammatory syndrome 1, proteasome-associated autoinflammatory syndrome 3, proteasome-associated autoinflammatory syndrome 2, proteasome-associated autoinflammatory syndrome 6

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

179 retrieved; paginated sample, class counts are floors:

75 likely benign, 62 uncertain significance, 14 conflicting classifications of pathogenicity, 12 pathogenic, 6 benign/likely benign, 5 benign, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1385379	NM_148919.4(PSMB8):c.481C>T (p.Gln161Ter)	PSMB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2768840	NM_148919.4(PSMB8):c.227_230dup (p.Phe78fs)	PSMB8	Pathogenic	criteria provided, single submitter
2818532	NM_148919.4(PSMB8):c.108_118del (p.Met37fs)	PSMB8	Pathogenic	criteria provided, single submitter
2844110	NM_148919.4(PSMB8):c.383del (p.Glu128fs)	PSMB8	Pathogenic	criteria provided, single submitter
2860423	NM_148919.4(PSMB8):c.50C>A (p.Ser17Ter)	PSMB8	Pathogenic	criteria provided, single submitter
29862	NM_148919.4(PSMB8):c.405C>A (p.Cys135Ter)	PSMB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3641579	NM_148919.4(PSMB8):c.337del (p.Leu113fs)	PSMB8	Pathogenic	criteria provided, single submitter
3645559	NM_148919.4(PSMB8):c.21C>A (p.Cys7Ter)	PSMB8	Pathogenic	criteria provided, single submitter
3672941	NM_148919.4(PSMB8):c.636_643del (p.Asp212fs)	PSMB8	Pathogenic	criteria provided, single submitter
3712361	NM_148919.4(PSMB8):c.31C>T (p.Arg11Ter)	PSMB8	Pathogenic	criteria provided, single submitter
3712942	NM_148919.4(PSMB8):c.434del (p.Arg145fs)	PSMB8	Pathogenic	criteria provided, single submitter
659832	NM_148919.4(PSMB8):c.224C>T (p.Thr75Met)	PSMB8	Pathogenic	criteria provided, multiple submitters, no conflicts
933294	NM_148919.4(PSMB8):c.608_611dup (p.Asn204fs)	PSMB8	Pathogenic	criteria provided, single submitter
952176	NM_148919.4(PSMB8):c.421C>T (p.Arg141Ter)	PSMB8	Pathogenic	criteria provided, single submitter
2027149	NM_148919.4(PSMB8):c.69_147+42del	PSMB8	Likely pathogenic	criteria provided, single submitter
3246001	NC_000006.11:g.(?32810848)(32811339_?)del	PSMB8	Likely pathogenic	criteria provided, single submitter
4797186	NM_148919.4(PSMB8):c.147+1G>T	PSMB8	Likely pathogenic	criteria provided, single submitter
1090767	NM_148919.4(PSMB8):c.537+8C>T	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1093565	NM_148919.4(PSMB8):c.756G>A (p.Lys252=)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1691062	NM_148919.4(PSMB8):c.31dup (p.Arg11fs)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694137	NM_148919.4(PSMB8):c.240C>T (p.Phe80=)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1694139	NM_148919.4(PSMB8):c.407+7G>A	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2080148	NM_148919.4(PSMB8):c.647G>A (p.Arg216Gln)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3245999	NC_000006.11:g.(?32796632)(32808844_?)del	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356361	NM_148919.4(PSMB8):c.804G>A (p.Leu268=)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356362	NM_148919.4(PSMB8):c.701A>G (p.Tyr234Cys)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356363	NM_148919.4(PSMB8):c.686G>A (p.Arg229His)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
465423	NM_148919.4(PSMB8):c.815G>A (p.Arg272Gln)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
907465	NM_148919.4(PSMB8):c.180C>T (p.Asp60=)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
940811	NM_148919.4(PSMB8):c.181G>A (p.Gly61Arg)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PSMB8	Definitive	Autosomal recessive	proteasome-associated autoinflammatory syndrome 1	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PSMB8	Orphanet:324977	Proteasome-associated autoinflammatory syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSMB8	HGNC:9545	ENSG00000204264	P28062	Proteasome subunit beta type-8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSMB8	Proteasome subunit beta type-8	The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMB8	Other/Unknown	no		Pept_T1A_subB, Proteasome_sua/b, Proteasome_bsu_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
spleen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMB8	132	ubiquitous	marker	granulocyte, leukocyte, spleen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMB8	3,188

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMB8	P28062	22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Antigen processing: Ub, ATP-independent proteasomal degradation	1	571.0×	0.008	PSMB8
Cross-presentation of soluble exogenous antigens (endosomes)	1	253.8×	0.008	PSMB8
Proteasome assembly	1	203.9×	0.008	PSMB8
Interferon alpha/beta signaling	1	152.3×	0.008	PSMB8
ER-Phagosome pathway	1	129.8×	0.008	PSMB8

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
antigen processing and presentation	1	702.2×	0.004	PSMB8
fat cell differentiation	1	181.2×	0.008	PSMB8
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.019	PSMB8

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PSMB8	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMB8	7	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMB8
CARFILZOMIB	4	PSMB8
IXAZOMIB	3	PSMB8
MARIZOMIB	3	PSMB8
OPROZOMIB	2	PSMB8
DELANZOMIB	2	PSMB8
ZETOMIPZOMIB	2	PSMB8

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
PSMB8	262	Binding:250, ADMET:9, Functional:3

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
PSMB8	262

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

7 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
BORTEZOMIB	4	PSMB8
CARFILZOMIB	4	PSMB8
IXAZOMIB	3	PSMB8
MARIZOMIB	3	PSMB8
OPROZOMIB	2	PSMB8
DELANZOMIB	2	PSMB8
ZETOMIPZOMIB	2	PSMB8

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PSMB8
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2/PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04517253	PHASE2/PHASE3	TERMINATED	A Study of Baricitinib (LY3009104) in Adult and Pediatric Japanese Participants With NNS/CANDLE, SAVI, and AGS
NCT01724580	Not specified	APPROVED_FOR_MARKETING	Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BARICITINIB	4	2
CHEMBL5427854	0	1