Proteasome-associated autoinflammatory syndrome 1

Summary

Proteasome-associated autoinflammatory syndrome 1 (MONDO:0054698) is a disease caused by PSMB8 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: PSMB8 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 66

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	proteasome-associated autoinflammatory syndrome 1
Mondo ID	MONDO:0054698
OMIM	256040
NCIT	C176619
UMLS	C4746851
MedGen	1648310
GARD	0003916
Is cancer (heuristic)	no

Also known as: PRAAS1 · proteasome-associated autoinflammatory syndrome 1 · proteasome-associated autoinflammatory syndrome 1 and digenic forms

Data availability: 66 ClinVar variants · 5 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › proteosome-associated autoinflammatory syndrome › proteasome-associated autoinflammatory syndrome 1

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

66 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 9 conflicting classifications of pathogenicity, 6 pathogenic, 6 benign, 6 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
548958	NM_002796.3(PSMB4):c.666C>A (p.Tyr222Ter)	PSMB4	Pathogenic	no assertion criteria provided
29860	NM_148919.4(PSMB8):c.602G>T (p.Gly201Val)	PSMB8	Pathogenic	no assertion criteria provided
29862	NM_148919.4(PSMB8):c.405C>A (p.Cys135Ter)	PSMB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3220940	NM_148919.4(PSMB8):c.163C>T (p.Gln55Ter)	PSMB8	Pathogenic	no assertion criteria provided
3220941	NM_148919.4(PSMB8):c.352T>C (p.Ser118Pro)	PSMB8	Pathogenic	no assertion criteria provided
548954	NM_148919.4(PSMB8):c.313A>C (p.Lys105Gln)	PSMB8	Pathogenic	no assertion criteria provided
659832	NM_148919.4(PSMB8):c.224C>T (p.Thr75Met)	PSMB8	Pathogenic	criteria provided, multiple submitters, no conflicts
3064774	NM_004159.5(PSMB8):c.107_108del (p.Pro36fs)	PSMB8	Likely pathogenic	criteria provided, single submitter
1691062	NM_148919.4(PSMB8):c.31dup (p.Arg11fs)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356359	NM_148919.4(PSMB8):c.*8G>A	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
356360	NM_148919.4(PSMB8):c.*6G>C	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
961098	NM_148919.4(PSMB8):c.662C>T (p.Pro221Leu)	PSMB8	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2427350	NC_000006.11:g.(?30695893)(36953949_?)dup	LHFPL5	Uncertain significance	criteria provided, single submitter
1009278	NM_148919.4(PSMB8):c.422G>A (p.Arg141Gln)	PSMB8	Uncertain significance	criteria provided, single submitter
1021668	NM_148919.4(PSMB8):c.666A>C (p.Glu222Asp)	PSMB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1034913	NM_148919.4(PSMB8):c.625G>C (p.Gly209Arg)	PSMB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1053378	NM_148919.4(PSMB8):c.798C>G (p.Asp266Glu)	PSMB8	Uncertain significance	criteria provided, single submitter
1062161	NM_148919.4(PSMB8):c.100A>G (p.Ser34Gly)	PSMB8	Uncertain significance	criteria provided, single submitter
1402300	NM_148919.4(PSMB8):c.154G>A (p.Glu52Lys)	PSMB8	Uncertain significance	criteria provided, single submitter
1441295	NM_148919.4(PSMB8):c.710A>G (p.His237Arg)	PSMB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
1693911	NM_148919.4(PSMB8):c.271C>T (p.Arg91Trp)	PSMB8	Uncertain significance	criteria provided, multiple submitters, no conflicts
2419153	NM_148919.4(PSMB8):c.646C>T (p.Arg216Trp)	PSMB8	Uncertain significance	criteria provided, single submitter
3242008	NM_148919.4(PSMB8):c.826C>G (p.Gln276Glu)	PSMB8	Uncertain significance	criteria provided, single submitter
356357	NM_148919.4(PSMB8):c.*178G>A	PSMB8	Uncertain significance	criteria provided, single submitter
356367	NM_148919.4(PSMB8):c.167C>A (p.Ser56Tyr)	PSMB8	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
LHFPL5	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PSMB8	HGNC:9545	ENSG00000204264	P28062	Proteasome subunit beta type-8	gencc,clinvar
LHFPL5	HGNC:21253	ENSG00000197753	Q8TAF8	LHFPL tetraspan subfamily member 5 protein	clinvar
PSMB4	HGNC:9541	ENSG00000159377	P28070	Proteasome subunit beta type-4	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.
LHFPL5	LHFPL tetraspan subfamily member 5 protein	Auxiliary subunit of the mechanotransducer (MET) non-specific cation channel complex located at the tips of the shorter stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.
PSMB4	Proteasome subunit beta type-4	Non-catalytic component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PSMB8	Other/Unknown	no		Pept_T1A_subB, Proteasome_sua/b, Proteasome_bsu_CS
LHFPL5	Other/Unknown	no		LHFPL
PSMB4	Other/Unknown	no		Proteasome_sua/b, Proteasome_bsu_CS, Proteasome_beta4

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
leukocyte	1
spleen	1
body of pancreas	1
male germ line stem cell (sensu Vertebrata) in testis	1
pancreas	1
endometrium epithelium	1
epithelium of nasopharynx	1
nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PSMB8	132	ubiquitous	marker	granulocyte, leukocyte, spleen
LHFPL5	161	tissue_specific	marker	body of pancreas, male germ line stem cell (sensu Vertebrata) in testis, pancreas
PSMB4	300	ubiquitous	marker	epithelium of nasopharynx, endometrium epithelium, nasopharynx

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PSMB4	3,606
PSMB8	3,188
LHFPL5	1,169

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PSMB4	P28070	146
PSMB8	P28062	22

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LHFPL5	Q8TAF8	89.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 73. Enrichment computed across 3 evidence-associated genes (3 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 3 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	380.7×	6e-04	PSMB8, PSMB4
Cross-presentation of soluble exogenous antigens (endosomes)	2	169.2×	0.002	PSMB8, PSMB4
Proteasome assembly	2	135.9×	0.002	PSMB8, PSMB4
ER-Phagosome pathway	2	86.5×	0.003	PSMB8, PSMB4
Sensory processing of sound	1	102.9×	0.025	LHFPL5
Regulation of activated PAK-2p34 by proteasome mediated degradation	1	92.8×	0.025	PSMB4
Regulation of ornithine decarboxylase (ODC)	1	90.6×	0.025	PSMB4
Vpu mediated degradation of CD4	1	88.5×	0.025	PSMB4
Autodegradation of the E3 ubiquitin ligase COP1	1	88.5×	0.025	PSMB4
Ubiquitin-dependent degradation of Cyclin D	1	88.5×	0.025	PSMB4
Vif-mediated degradation of APOBEC3G	1	84.6×	0.025	PSMB4
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	82.8×	0.025	PSMB4
Degradation of AXIN	1	82.8×	0.025	PSMB4
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	1	82.8×	0.025	PSMB4
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	1	82.8×	0.025	PSMB4
Hh mutants are degraded by ERAD	1	81.0×	0.025	PSMB4
SCF-beta-TrCP mediated degradation of Emi1	1	79.3×	0.025	PSMB4
Degradation of DVL	1	79.3×	0.025	PSMB4
Negative regulation of NOTCH4 signaling	1	79.3×	0.025	PSMB4
GSK3B-mediated proteasomal degradation of PD-L1(CD274)	1	79.3×	0.025	PSMB4
Regulation of RUNX3 expression and activity	1	77.7×	0.025	PSMB4
Somitogenesis	1	77.7×	0.025	PSMB4
NIK–>noncanonical NF-kB signaling	1	76.1×	0.025	PSMB4
SPOP-mediated proteasomal degradation of PD-L1(CD274)	1	76.1×	0.025	PSMB4
Degradation of GLI1 by the proteasome	1	74.6×	0.025	PSMB4
Degradation of GLI2 by the proteasome	1	74.6×	0.025	PSMB4
GLI3 is processed to GLI3R by the proteasome	1	74.6×	0.025	PSMB4
Defective CFTR causes cystic fibrosis	1	73.2×	0.025	PSMB4
Degradation of CRY and PER proteins	1	73.2×	0.025	PSMB4
Dectin-1 mediated noncanonical NF-kB signaling	1	71.8×	0.025	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
detection of mechanical stimulus involved in sensory perception	1	936.2×	0.005	LHFPL5
proteasome-mediated ubiquitin-dependent protein catabolic process	2	34.8×	0.005	PSMB8, PSMB4
detection of mechanical stimulus involved in sensory perception of sound	1	312.1×	0.007	LHFPL5
auditory receptor cell stereocilium organization	1	280.9×	0.007	LHFPL5
antigen processing and presentation	1	234.1×	0.007	PSMB8
negative regulation of inflammatory response to antigenic stimulus	1	200.6×	0.007	PSMB4
fat cell differentiation	1	60.4×	0.021	PSMB8
monoatomic ion transport	1	52.0×	0.021	LHFPL5
sensory perception of sound	1	33.6×	0.029	LHFPL5

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
PSMB4	BORTEZOMIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PSMB8	7	4
PSMB4	5	4
LHFPL5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BORTEZOMIB	4	PSMB4, PSMB8
CARFILZOMIB	4	PSMB4, PSMB8
IXAZOMIB	3	PSMB4, PSMB8
MARIZOMIB	3	PSMB4, PSMB8
OPROZOMIB	2	PSMB4, 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
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
PSMB8	262
PSMB4	171

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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, PSMB8
CARFILZOMIB	4	PSMB4, PSMB8
IXAZOMIB	3	PSMB4, PSMB8
MARIZOMIB	3	PSMB4, PSMB8
OPROZOMIB	2	PSMB4, 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)	2	PSMB8, PSMB4
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	1	LHFPL5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LHFPL5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.