SQSTM1-related multisystem proteinopathy

Summary

SQSTM1-related multisystem proteinopathy (MONDO:0800464) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	SQSTM1-related multisystem proteinopathy
Mondo ID	MONDO:0800464
GARD	0026565
Is cancer (heuristic)	no

Also known as: SQSTM1-related multisystem proteinopathy

Data availability: 2 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › SQSTM1-related multisystem proteinopathy

Related subtypes (92): thiopurine metabolic disease, hypercalcemia, infantile, hypermanganesemia with dystonia, abdominal obesity-metabolic syndrome, plasma protein metabolism disease, inherited lipid metabolism disorder, lysosomal storage disease, striatonigral degeneration, inborn metal metabolism disorder, inborn vitamin metabolic disorder, chondrocalcinosis 2, Ehlers-Danlos syndrome, spondylodysplastic type, fish eye disease, aromatase excess syndrome, spondyloepiphyseal dysplasia with congenital joint dislocations, hypertriglyceridemia 1, autosomal dominant myoglobinuria, diastrophic dysplasia, hemolytic anemia due to diphosphoglycerate mutase deficiency, multiple epiphyseal dysplasia type 4, atelosteogenesis type II, inherited threoninemia, inborn glycerol kinase deficiency, achondrogenesis type IB, diabetes mellitus, noninsulin-dependent, 1, diabetes mellitus, noninsulin-dependent, 2, renal tubular acidosis, distal, 3, with or without sensorineural hearing loss, diabetes mellitus, noninsulin-dependent, 3, hypercholesterolemia, familial, 4, hypoalphalipoproteinemia, primary, 1, autosomal recessive proximal renal tubular acidosis, diabetes mellitus, noninsulin-dependent, 4, normophosphatemic familial tumoral calcinosis, apolipoprotein c-III deficiency, hypotonia-failure to thrive-microcephaly syndrome, chondrodysplasia with joint dislocations, gPAPP type, gluthathione peroxidase deficiency, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diabetes mellitus, noninsulin-dependent, 5, congenital disorder of glycosylation, monogenic diabetes, 2-hydroxyglutaric aciduria, familial hypoparathyroidism, familial intrahepatic cholestasis, inborn aminoacylase deficiency, disorder of lysosomal-related organelles, inborn disorder of porphyrin metabolism, disorder of metabolite absorption and transport, autosomal dominant proximal renal tubular acidosis, neurodegeneration with brain iron accumulation, ferro-cerebro-cutaneous syndrome, familial hypocalciuric hypercalcemia, hypophosphatasia, hereditary amyloidosis, peroxisomal disease, inborn disorder of amino acid and other organic acid metabolism, inborn carbohydrate metabolic disorder, inborn disorder of energy metabolism, inborn disorder of biogenic amine metabolism and transport, inborn disorder of purine or pyrimidine metabolism, spondyloepimetaphyseal dysplasia, PAPSS2 type, hereditary lipodystrophy, hereditary recurrent myoglobinuria, DNA repair disease, 4-hydroxyphenylacetic aciduria, 5-nucleotidase syndrome, antigen-peptide-transporter 2 deficiency, APO A-i deficiency, cardiomyopathy hypogonadism metabolic anomalies, deficiency of coenzyme q cytochrome c reductase, defective apolipoprotein b-100, sulfide quinone oxidoreductase deficiency, congenital disorder of deglycosylation, hypoalphalipoproteinemia, primary, 2, uridine-cytidineuria, NAD(P)HX dehydratase deficiency, inborn disorder of aspartate family metabolism, weinstein kliman scully syndrome, glycoprotein metabolism disease, inherited thyroid metabolism disease, tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 3, combined ApoA-I and ApoC-III deficiency, familial hyperphosphatemic tumoral calcinosis/hyperphosphatemic hyperostosis syndrome, tumoral calcinosis, hyperphosphatemic, familial, 1, Waldenstrom macroglobulinemia, mucopolysaccharidosis or mucopolysaccharidosis-like disorder, disorder of peptide and amine metabolism, CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis, Lane Hamilton syndrome, hypertriglyceridemia 2, autosomal dominant dopa-responsive dystonia

Subtypes (3): Paget disease of bone 3, frontotemporal dementia and/or amyotrophic lateral sclerosis 3, myopathy, distal, with rimmed vacuoles

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

2 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1387627	NM_003900.5(SQSTM1):c.301+1G>T	SQSTM1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8108	NM_003900.5(SQSTM1):c.1175C>T (p.Pro392Leu)	SQSTM1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis

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
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf

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
left adrenal gland	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SQSTM1	7,269

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SQSTM1	Q13501	26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. 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
p75NTR signals via NF-kB	1	1903.3×	0.007	SQSTM1
Mitophagy	1	1038.2×	0.007	SQSTM1
Pexophagy	1	951.7×	0.007	SQSTM1
p75NTR recruits signalling complexes	1	878.5×	0.007	SQSTM1
NF-kB is activated and signals survival	1	878.5×	0.007	SQSTM1
NRIF signals cell death from the nucleus	1	713.8×	0.007	SQSTM1
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.010	SQSTM1
Nuclear events mediated by NFE2L2	1	335.9×	0.010	SQSTM1
Selective autophagy	1	278.5×	0.010	SQSTM1
Interleukin-1 family signaling	1	271.9×	0.010	SQSTM1
Signaling by ALK in cancer	1	271.9×	0.010	SQSTM1
Cell death signalling via NRAGE, NRIF and NADE	1	219.6×	0.012	SQSTM1
p75 NTR receptor-mediated signalling	1	187.2×	0.013	SQSTM1
Signaling by ALK fusions and activated point mutants	1	150.3×	0.013	SQSTM1
Autophagy	1	148.3×	0.013	SQSTM1
Cellular response to chemical stress	1	142.8×	0.013	SQSTM1
Death Receptor Signaling	1	139.3×	0.013	SQSTM1
Interleukin-1 signaling	1	124.1×	0.013	SQSTM1
KEAP1-NFE2L2 pathway	1	120.2×	0.013	SQSTM1
Macroautophagy	1	115.3×	0.013	SQSTM1
Signaling by Interleukins	1	64.2×	0.023	SQSTM1
Diseases of signal transduction by growth factor receptors and second messengers	1	56.8×	0.025	SQSTM1
Neddylation	1	47.4×	0.028	SQSTM1
Cytokine Signaling in Immune system	1	40.8×	0.032	SQSTM1
Cellular responses to stress	1	36.8×	0.034	SQSTM1
Cellular responses to stimuli	1	31.5×	0.038	SQSTM1
Post-translational protein modification	1	19.2×	0.060	SQSTM1
Disease	1	13.1×	0.082	SQSTM1
Immune System	1	13.0×	0.082	SQSTM1
Metabolism of proteins	1	12.4×	0.084	SQSTM1

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
brown fat cell proliferation	1	5617.3×	0.003	SQSTM1
protein targeting to vacuole involved in autophagy	1	5617.3×	0.003	SQSTM1
response to mitochondrial depolarisation	1	2808.7×	0.004	SQSTM1
regulation of Ras protein signal transduction	1	1872.4×	0.004	SQSTM1
aggrephagy	1	1685.2×	0.004	SQSTM1
protein localization to perinuclear region of cytoplasm	1	1404.3×	0.004	SQSTM1
negative regulation of toll-like receptor 4 signaling pathway	1	1123.5×	0.004	SQSTM1
membraneless organelle assembly	1	1123.5×	0.004	SQSTM1
pexophagy	1	1053.2×	0.004	SQSTM1
regulation of protein complex stability	1	1053.2×	0.004	SQSTM1
regulation of mitochondrion organization	1	842.6×	0.004	SQSTM1
cellular response to stress	1	842.6×	0.004	SQSTM1
negative regulation of ferroptosis	1	802.5×	0.004	SQSTM1
autophagy of mitochondrion	1	732.7×	0.004	SQSTM1
positive regulation of long-term synaptic potentiation	1	674.1×	0.004	SQSTM1
temperature homeostasis	1	648.1×	0.004	SQSTM1
regulation of canonical NF-kappaB signal transduction	1	481.5×	0.005	SQSTM1
immune system process	1	391.9×	0.005	SQSTM1
endosome organization	1	374.5×	0.005	SQSTM1
mitophagy	1	318.0×	0.006	SQSTM1
negative regulation of protein ubiquitination	1	285.6×	0.006	SQSTM1
energy homeostasis	1	271.8×	0.006	SQSTM1
positive regulation of protein localization to plasma membrane	1	271.8×	0.006	SQSTM1
response to ischemia	1	251.5×	0.006	SQSTM1
endosomal transport	1	244.2×	0.006	SQSTM1
macroautophagy	1	240.7×	0.006	SQSTM1
protein catabolic process	1	237.3×	0.006	SQSTM1
positive regulation of autophagy	1	208.1×	0.007	SQSTM1
protein import into nucleus	1	144.0×	0.009	SQSTM1
autophagy	1	110.1×	0.012	SQSTM1

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SQSTM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SQSTM1	20	Binding:20

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

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	SQSTM1

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)
SQSTM1	20	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.