Proteasome-associated autoinflammatory syndrome 3

Summary

Proteasome-associated autoinflammatory syndrome 3 (MONDO:0054699) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 9

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	proteasome-associated autoinflammatory syndrome 3
Mondo ID	MONDO:0054699
OMIM	617591
DOID	DOID:0060916
UMLS	C4747850
MedGen	1648456
GARD	0018446
Is cancer (heuristic)	no

Also known as: PRAAS3 · proteasome-associated autoinflammatory syndrome 3 · proteasome-associated autoinflammatory syndrome 3 and digenic forms

Data availability: 9 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › proteosome-associated autoinflammatory syndrome › proteasome-associated autoinflammatory syndrome 3

Related subtypes (5): proteasome-associated autoinflammatory syndrome 5, proteasome-associated autoinflammatory syndrome 4, proteasome-associated autoinflammatory syndrome 1, 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

9 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 benign, 2 benign/likely benign, 1 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
548955	NM_002796.3(PSMB4):c.636_644del (p.Asp212_Val214del)	PSMB4	Pathogenic	no assertion criteria provided
548995	NM_002800.5(PSMB9):c.494G>A (p.Gly165Asp)	PSMB9	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1032848	NM_002796.3(PSMB4):c.472G>A (p.Gly158Arg)	PSMB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
548956	NM_002796.3(PSMB4):c.-9G>A	PSMB4	Uncertain significance	criteria provided, multiple submitters, no conflicts
548957	NM_002796.3(PSMB4):c.44dup (p.Pro16fs)	PSMB4	Uncertain significance	criteria provided, single submitter
1165733	NM_002796.3(PSMB4):c.75G>A (p.Pro25=)	PSMB4	Benign	criteria provided, multiple submitters, no conflicts
1166562	NM_002796.3(PSMB4):c.701T>C (p.Ile234Thr)	PSMB4	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1327453	NM_002796.3(PSMB4):c.495-40T>C	PSMB4	Benign	criteria provided, multiple submitters, no conflicts
1327454	NM_002800.5(PSMB9):c.179G>A (p.Arg60His)	PSMB9	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 0 · 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
PSMB9	Strong	Autosomal dominant	proteasome-associated autoinflammatory syndrome 6	2
PSMB4	Limited	Autosomal recessive	proteasome-associated autoinflammatory syndrome 3	2

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSMB4	HGNC:9541	ENSG00000159377	P28070	Proteasome subunit beta type-4	gencc,clinvar
PSMB9	HGNC:9546	ENSG00000240065	P28065	Proteasome subunit beta type-9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PSMB4	Proteasome subunit beta type-4	Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins.
PSMB9	Proteasome subunit beta type-9	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: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMB4	Other/Unknown	no		Proteasome_sua/b, Proteasome_bsu_CS, Proteasome_beta4
PSMB9	Other/Unknown	no		Pept_T1A_subB, Proteasome_sua/b, Proteasome_bsu_CS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
epithelium of nasopharynx	1
nasopharynx	1
granulocyte	1
leukocyte	1
monocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMB4	300	ubiquitous	marker	epithelium of nasopharynx, endometrium epithelium, nasopharynx
PSMB9	133	ubiquitous	marker	granulocyte, leukocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMB4	3,606
PSMB9	2,896

Intra-cohort edges

A	B	Sources
PSMB4	PSMB9	biogrid_interaction, intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMB4	P28070	146
PSMB9	P28065	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 2 evidence-associated genes (2 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 2 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	2	571.0×	2e-04	PSMB4, PSMB9
Cross-presentation of soluble exogenous antigens (endosomes)	2	253.8×	5e-04	PSMB4, PSMB9
Proteasome assembly	2	203.9×	5e-04	PSMB4, PSMB9
ER-Phagosome pathway	2	129.8×	1e-03	PSMB4, PSMB9
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	139.3×	0.017	PSMB4
Regulation of ornithine decarboxylase (ODC)	1	135.9×	0.017	PSMB4
Vpu mediated degradation of CD4	1	132.8×	0.017	PSMB4
Autodegradation of the E3 ubiquitin ligase COP1	1	132.8×	0.017	PSMB4
Ubiquitin-dependent degradation of Cyclin D	1	132.8×	0.017	PSMB4
Vif-mediated degradation of APOBEC3G	1	126.9×	0.017	PSMB4
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	124.1×	0.017	PSMB4
Degradation of AXIN	1	124.1×	0.017	PSMB4
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	124.1×	0.017	PSMB4
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	124.1×	0.017	PSMB4
Hh mutants are degraded by ERAD	1	121.5×	0.017	PSMB4
SCF-beta-TrCP mediated degradation of Emi1	1	119.0×	0.017	PSMB4
Degradation of DVL	1	119.0×	0.017	PSMB4
Negative regulation of NOTCH4 signaling	1	119.0×	0.017	PSMB4
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	119.0×	0.017	PSMB4
Regulation of RUNX3 expression and activity	1	116.5×	0.017	PSMB4
Somitogenesis	1	116.5×	0.017	PSMB4
NIK–>noncanonical NF-kB signaling	1	114.2×	0.017	PSMB4
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	114.2×	0.017	PSMB4
Degradation of GLI1 by the proteasome	1	112.0×	0.017	PSMB4
Degradation of GLI2 by the proteasome	1	112.0×	0.017	PSMB4
GLI3 is processed to GLI3R by the proteasome	1	112.0×	0.017	PSMB4
Defective CFTR causes cystic fibrosis	1	109.8×	0.017	PSMB4
Degradation of CRY and PER proteins	1	109.8×	0.017	PSMB4
Dectin-1 mediated noncanonical NF-kB signaling	1	107.7×	0.017	PSMB4
Hedgehog ligand biogenesis	1	105.7×	0.017	PSMB4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
proteasome-mediated ubiquitin-dependent protein catabolic process	2	52.2×	0.001	PSMB4, PSMB9
negative regulation of inflammatory response to antigenic stimulus	1	300.9×	0.005	PSMB4
immune system process	1	195.9×	0.005	PSMB9

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 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
PSMB4	BORTEZOMIB
PSMB9	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMB9	7	4
PSMB4	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMB4, PSMB9
CARFILZOMIB	4	PSMB4, PSMB9
IXAZOMIB	3	PSMB4, PSMB9
MARIZOMIB	3	PSMB4, PSMB9
OPROZOMIB	2	PSMB4, PSMB9
DELANZOMIB	2	PSMB9
ZETOMIPZOMIB	2	PSMB9

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PSMB9	220	Binding:210, ADMET:7, Functional:3
PSMB4	171	Binding:162, ADMET:6, Functional:3

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PSMB4	171
PSMB9	220

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	PSMB4, PSMB9
CARFILZOMIB	4	PSMB4, PSMB9
IXAZOMIB	3	PSMB4, PSMB9
MARIZOMIB	3	PSMB4, PSMB9
OPROZOMIB	2	PSMB4, PSMB9
DELANZOMIB	2	PSMB9
ZETOMIPZOMIB	2	PSMB9

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	PSMB4, PSMB9
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: 0.