SQSTM1

Summary

SQSTM1 (sequestosome 1, HGNC:11280) is a protein-coding gene on chromosome 5q35.3, encoding Sequestosome-1 (Q13501). Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.

This gene encodes a multifunctional protein that binds ubiquitin and regulates activation of the nuclear factor kappa-B (NF-kB) signaling pathway. The protein functions as a scaffolding/adaptor protein in concert with TNF receptor-associated factor 6 to mediate activation of NF-kB in response to upstream signals. Alternatively spliced transcript variants encoding either the same or different isoforms have been identified for this gene. Mutations in this gene result in sporadic and familial Paget disease of bone.

Source: NCBI Gene 8878 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (Definitive, GenCC) — +6 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 870 total — 39 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 149
• Druggable target: yes
• MANE Select transcript: NM_003900

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11280
Approved symbol	SQSTM1
Name	sequestosome 1
Location	5q35.3
Locus type	gene with protein product
Status	Approved
Aliases	p62, p60, p62B, A170
Ensembl gene	ENSG00000161011
Ensembl biotype	protein_coding
OMIM	601530
Entrez	8878

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000360718, ENST00000389805, ENST00000422245, ENST00000453046, ENST00000464493, ENST00000466342, ENST00000481335, ENST00000485412, ENST00000504627, ENST00000506042, ENST00000506690, ENST00000508284, ENST00000510187, ENST00000512234, ENST00000514093, ENST00000626660, ENST00000884698, ENST00000884699, ENST00000884700, ENST00000884701, ENST00000884702, ENST00000884703, ENST00000884704, ENST00000884705, ENST00000951526, ENST00000951527

RefSeq mRNA: 3 — MANE Select: NM_003900 NM_001142298, NM_001142299, NM_003900

CCDS: CCDS34317, CCDS47355

Canonical transcript exons

ENST00000389805 — 8 exons

Exon	Start	End
ENSE00001506956	179836436	179838078
ENSE00002209764	179833587	179833782
ENSE00002271178	179833032	179833246
ENSE00002710344	179820905	179821141
ENSE00003525409	179822958	179823053
ENSE00003529424	179823858	179824087
ENSE00003787017	179824182	179824323
ENSE00003791241	179825146	179825226

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 99.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 426.2660 / max 3346.1581, expressed in 1829 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
60609	413.3381	1829
60599	5.9701	1752
60600	2.0662	1299
60611	1.5675	800
60608	0.6121	316
60612	0.6078	381
60615	0.5850	373
60616	0.5681	322
60613	0.4366	221
60614	0.4365	245

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	99.52	gold quality
right adrenal gland	UBERON:0001233	99.49	gold quality
left adrenal gland	UBERON:0001234	99.44	gold quality
left adrenal gland cortex	UBERON:0035825	99.37	gold quality
stromal cell of endometrium	CL:0002255	99.36	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.34	gold quality
right lobe of thyroid gland	UBERON:0001119	99.33	gold quality
left lobe of thyroid gland	UBERON:0001120	99.33	gold quality
gall bladder	UBERON:0002110	99.30	gold quality
mucosa of stomach	UBERON:0001199	99.24	gold quality
descending thoracic aorta	UBERON:0002345	99.21	gold quality
popliteal artery	UBERON:0002250	99.19	gold quality
tibial artery	UBERON:0007610	99.19	gold quality
endocervix	UBERON:0000458	99.18	gold quality
gastrocnemius	UBERON:0001388	99.18	gold quality
thoracic aorta	UBERON:0001515	99.15	gold quality
ascending aorta	UBERON:0001496	99.14	gold quality
right coronary artery	UBERON:0001625	99.14	gold quality
body of stomach	UBERON:0001161	99.11	gold quality
aorta	UBERON:0000947	99.08	gold quality
islet of Langerhans	UBERON:0000006	99.07	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.07	gold quality
minor salivary gland	UBERON:0001830	99.05	gold quality
upper lobe of left lung	UBERON:0008952	99.05	gold quality
lower esophagus	UBERON:0013473	99.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.04	gold quality
ectocervix	UBERON:0012249	99.01	gold quality
body of pancreas	UBERON:0001150	99.00	gold quality
left coronary artery	UBERON:0001626	99.00	gold quality
apex of heart	UBERON:0002098	98.98	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	1229.03
E-HCAD-1	yes	29.43
E-CURD-46	yes	20.12
E-CURD-122	yes	9.38
E-MTAB-10042	yes	4.76
E-MTAB-6379	no	1063.45
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF4, CREB1, CTNNB1, ETS1, HBP1, MYC, NEUROD1, NFE2L2, NFKB1, NFKB, NR1H4, NR2C2, SP1, SP3, SPDEF, TCF20, TCF7L2, THRB, TP53

miRNA regulators (miRDB)

56 targeting SQSTM1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6134	99.63	65.68	1537

Literature-anchored findings (GeneRIF, showing 40)

• the constant presence of p62 in Mallory bodies suggests that binding of p62 to abnormal keratins may allow hepatocytes to dispose potentially harmful proteins in a biologically inert manner. (PMID:11981755)
• Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. (PMID:11992264)
• mutations affecting the ubiquitin-binding domain of SQSTM1 are a common cause of familial and sporadic Paget’s disease of bone (PMID:12374763)
• p62 protein is overexpressed in breast cancer. Its mRNA & protein increase in response to PSI. PDEF upregulates p62 promoter activity at 2 sites. PSI downregulates PDEF-induced p62 promoter activation through one of these sites. (PMID:12700667)
• In frontotemporal dementia, the degenerative process involves p62, and the process takes place not only in neurons but also in glial cells. (PMID:12727313)
• structure of the ubiquitin-associated domain of p62 (SQSTM1) and implications for mutations that cause Paget’s disease of bone (PMID:12857745)
• functional ubiquitin-binding motifs in Atx-3 and p62 proteins are required for the localization of both proteins into aggregates (PMID:12857950)
• SQSTM1 mutations may play a role in the majority of familial Paget’s disease of bone (PMID:14584883)
• During formation of Lewy bodies associated with Parkinson disease the most robust immunoreactivity for p62 is seen in small intranuclear inclusions distinctly outlined, with spherical, uniformly staining bodies. (PMID:14692700)
• minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget’s cases (PMID:15125799)
• causal role of SQSTM1 gene mutations in the pathogenesis of Paget’s disease (PMID:15146436)
• The SQSTM1 P392L mutation is a recurrent mutation causing Paget’s Disease of bone in different populations. We were not able to show an association between SQSTM1 polymorphisms and PDB in our population. (PMID:15164150)
• p62 may act as a critical ubiquitin chain-targeting factor that shuttles substrates for proteasomal degradation (PMID:15340068)
• mutations in the UBA domain of SQSTM1 (p62) have effects on binding sites and secondary structure and have a role in Paget’s disease of bone [review] (PMID:15493999)
• a founder effect may be responsible for teh SQSTM1 P392L mutation in Paget’s disease of bone patients of British descent, irrespective of family history (PMID:15647816)
• Sequestosome 1/p62 is co-localized with ubiquitinated proteins and UCH-L1 in cytoplasmic aggregates induced by PGJ2. Preventing sequestosome 1/p62 up-regulation by RNAi abolishes aggregation but not increase of ubiquitinated proteins or PGJ2 toxicity. (PMID:15911346)
• p62 interacts with lysine63-polyubiquitinated tau through its ubiquitin-associated (UBA) domain and serves a novel role in regulating tau proteasomal degradation. (PMID:15953362)
• Taken together, the data suggest p62 is a regulator of neuronal cell survival and differentiation. (PMID:16011831)
• p62 regulates nerve growth factor-induced NF-kappaB activation by influencing TRAF6 polyubiquitination (PMID:16079148)
• Results suggest that p62 fibrils may influence cell viability and indicates an important role for p62 in aggresome formation. (PMID:16129434)
• p62 may, via LC3, be involved in linking polyubiquitinated protein aggregates to the autophagy machinery and has a protective effect on huntingtin-induced cell death (PMID:16286508)
• Cytosolic overexpression of p62 is a novel immunohistochemical characteristic in prostatic adenocarcinoma and high-grade PIN, suggesting that p62 might be a novel marker for prostatic malignancy. (PMID:16405664)
• There is sound evidence incriminating Sequestosome 1 (SQSTM1) on the long arm of chromosome 5 (5q35-qter), of which nine mutations have been described in Paget’s disease of bone. (PMID:16574459)
• The disease mechanism in PDB with SQSTM1 mutations involves a loss of ubiquitin binding function of SQSTM1, implicating a sequence extrinsic to the compact globular region of the UBA domain as a critical determinant of ubiquitin recognition by SQSTM1. (PMID:16691492)
• Our results suggested that p62 plays important roles in forming the inclusions and may be associated with the protection of the neurons from degenerative processes involving ubiquitin. (PMID:16820172)
• Understanding how loss of ubiquitin-binding function of p62 impacts on signal transduction events in osteoclasts will further understanding Paget’s disease of bone at the molecular level. (PMID:17052185)
• G1205C splice site mutation probably disrupts the ubiquitin-binding properties of the protein. (PMID:17120186)
• Expression on osteoclasts is not sufficient to induce the full paget disease but p62 mutations cause a predisposition to the development of Paget disease by increasing the sensitivity of osteoclast precursors to osteoclastogenic cytokines. (PMID:17187080)
• frequency estimates for SQSTM1/p62 mutations and haplotype distribution in familial Paget’s disease of bone (PMID:17229007)
• p62, a ubiquitin proteasome system related protein, was found in the majority of Neurofibrillary Tangles , but in only a small proportion of neuronal alpha-synuclein inclusions in cases of combined multiple system atrophy and Alzheimer’s disease. (PMID:17237936)
• The specific interaction between p62 and LC3, mediated by a 22-residue sequence of p62 containing an evolutionarily conserved motif, is instrumental in mediating autophagic degradation of the p62-positive bodies. (PMID:17580304)
• Development of Mallory bodies requires overexpression of keratin 8, ubiquitin, and p62 containing the ubiquitin binding domain, whereas intracellular hyaline bodies result from overexpression of p62 together with ubiquitin without keratin involvement. (PMID:17685470)
• analyse the expression of p62 in muscle biopsies from patients suffering from myotilinopathy and desminopathy (PMID:17931355)
• The solution structure of a 52 residue construct containing the ubiquitin associated domain of p62 has been characterized using heteronuclear nuclear magnetic resonance (NMR) methods. (PMID:17932931)
• Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a novel conformational switch. (PMID:18083707)
• Frontotemporal lobar degeneration with ubiquitin-positive inclusions visualized with ubiquitin-binding protein p62. (PMID:18379439)
• analysis of sequestosome 1 (SQSTM1) mutations in Paget’s disease of bone from the United States (PMID:18379713)
• This study revealed genetic associations of SLC1A4, SQSTM1, and EIF4EBP1 with MSA. These results may lend genetic support to the hypothesis that oxidative stress is associated with the pathogenesis of MSA. (PMID:18442140)
• In this study, the lysine selection process for TRAF6/p62 ubiquitination was examined. (PMID:18457658)
• strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with Paget’s Disease of Bone (PMID:18543015)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	sqstm1	ENSDARG00000075014
mus_musculus	Sqstm1	ENSMUSG00000015837
rattus_norvegicus	Sqstm1	ENSRNOG00000003147
drosophila_melanogaster	ref(2)P	FBGN0003231
caenorhabditis_elegans		WBGENE00011737
caenorhabditis_elegans		WBGENE00012067
caenorhabditis_elegans		WBGENE00012516
caenorhabditis_elegans		WBGENE00015552
caenorhabditis_elegans		WBGENE00021495

Protein

Protein identifiers

Sequestosome-1 — Q13501 (reviewed: Q13501)

Alternative names: EBI3-associated protein of 60 kDa, Phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa, Ubiquitin-binding protein p62

All UniProt accessions (7): Q13501, C9J6J8, C9JRJ8, D6RBF1, E3W990, E7EMC7, E9PFW8

UniProt curated annotations — full annotation on UniProt →

Function. Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes. Promotes the recruitment of ubiquitinated cargo proteins to autophagosomes via multiple domains that bridge proteins and organelles in different steps. SQSTM1 first mediates the assembly and removal of ubiquitinated proteins by undergoing liquid-liquid phase separation upon binding to ubiquitinated proteins via its UBA domain, leading to the formation of insoluble cytoplasmic inclusions, known as p62 bodies. SQSTM1 then interacts with ATG8 family proteins on autophagosomes via its LIR motif, leading to p62 body recruitment to autophagosomes, followed by autophagic clearance of ubiquitinated proteins. SQSTM1 is itself degraded along with its ubiquitinated cargos. Also required to recruit ubiquitinated proteins to PML bodies in the nucleus. Also involved in autophagy of peroxisomes (pexophagy) in response to reactive oxygen species (ROS) by acting as a bridge between ubiquitinated PEX5 receptor and autophagosomes. Acts as an activator of the NFE2L2/NRF2 pathway via interaction with KEAP1: interaction inactivates the BCR(KEAP1) complex by sequestering the complex in inclusion bodies, promoting nuclear accumulation of NFE2L2/NRF2 and subsequent expression of cytoprotective genes. Promotes relocalization of ‘Lys-63’-linked ubiquitinated STING1 to autophagosomes. Involved in endosome organization by retaining vesicles in the perinuclear cloud: following ubiquitination by RNF26, attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Sequesters tensin TNS2 into cytoplasmic puncta, promoting TNS2 ubiquitination and proteasomal degradation. May regulate the activation of NFKB1 by TNF, nerve growth factor (NGF) and interleukin-1. May play a role in titin/TTN downstream signaling in muscle cells. Adapter that mediates the interaction between TRAF6 and CYLD.

Subunit / interactions. Homooligomer or heterooligomer; may form homotypic arrays. Dimerization interferes with ubiquitin binding. Component of a ternary complex with PAWR and PRKCZ. Forms a complex with JUB/Ajuba, PRKCZ and TRAF6. Identified in a complex with TRAF6 and CYLD. Identified in a heterotrimeric complex with ubiquitin and ZFAND5, where ZFAND5 and SQSTM1 both interact with the same ubiquitin molecule. Interacts (via LIR motif) with MAP1LC3A and MAP1LC3B, as well as with other ATG8 family members, including GABARAP, GABARAPL1 and GABARAPL2; these interactions are necessary for the recruitment MAP1 LC3 family members to inclusion bodies containing polyubiquitinated protein aggregates and for their degradation by autophagy. Interacts directly with PRKCI and PRKCZ. Interacts with EBI3, LCK, RASA1, NR2F2, NTRK1, NTRK2, NTRK3, NBR1, MAP2K5 and MAPKAPK5. Upon TNF stimulation, interacts with RIPK1 probably bridging IKBKB to the TNF-R1 complex composed of TNF-R1/TNFRSF1A, TRADD and RIPK1. Interacts with the proteasome subunits PSMD4 and PSMC2. Interacts with TRAF6. Interacts with ‘Lys-63’-linked polyubiquitinated MAPT/TAU. Interacts with FHOD3. Interacts with CYLD. Interacts with SESN1. Interacts with SESN2. Interacts with ULK1. Interacts with UBD. Interacts with WDR81; the interaction is direct and regulates the interaction of SQSTM1 with ubiquitinated proteins. Interacts with WDFY3; this interaction is required to recruit WDFY3 to cytoplasmic bodies and to PML bodies. Interacts with LRRC25. Interacts with STING1; leading to relocalization of STING1 to autophagosomes. Interacts (when phosphorylated at Ser-349) with KEAP1; the interaction is direct and inactivates the BCR(KEAP1) complex by sequestering KEAP1 in inclusion bodies, promoting its degradation. Interacts with MOAP1; promoting dissociation of SQSTM1 inclusion bodies that sequester KEAP1. Interacts with GBP1. Interacts with TAX1BP1. Interacts with (ubiquitinated) PEX5; specifically binds PEX5 ubiquitinated at ‘Lys-209’ in response to reactive oxygen species (ROS). Interacts (via PB1 domain) with TNS2; the interaction leads to sequestration of TNS2 in cytoplasmic aggregates with SQSTM1 and promotes TNS2 ubiquitination and proteasomal degradation. Interacts with IRS1; the interaction is disrupted by the presence of tensin TNS2. Interacts with TRIM5. Interacts with TRIM11 (when ubiquitinated); promoting AIM2 recruitment to autophagosomes and autophagy-dependent degradation of AIM2. Interacts with TRIM13. Interacts with TRIM16. Interacts with TRIM23. Interacts with TRIM50. Interacts with TRIM55. Interacts with ECSIT; this interaction inhibits TLR4 signaling via functional regulation of the TRAF6-ECSIT complex. Interacts with GABRR1, GABRR2 and GABRR3. Interacts with WDR83. Interacts with GRB2. Interacts with USP12; the interaction is independent of USP12 deubiquitinase activity and may be involved in regulation of autophagic flux. Interacts with ASB6.

Subcellular location. Cytoplasmic vesicle. Autophagosome. Preautophagosomal structure. Cytoplasm. Cytosol. Nucleus. PML body. Late endosome. Lysosome. Endoplasmic reticulum. Myofibril. Sarcomere.

Tissue specificity. Ubiquitously expressed.

Post-translational modifications. Phosphorylation at Ser-407 by ULK1 destabilizes the UBA dimer interface and increases binding affinity to ubiquitinated proteins. Phosphorylation at Ser-407 also primes for subsequent phosphorylation at Ser-403. Phosphorylation at Ser-403 by CK2 or ULK1 promotes binding to ubiquitinated proteins by increasing the affinity between the UBA domain and polyubiquitin chains. Phosphorylation at Ser-403 by ULK1 is stimulated by SESN2. Phosphorylated at Ser-403 by TBK1, leading to promote relocalization of ‘Lys-63’-linked ubiquitinated STING1 to autophagosomes. Phosphorylation at Ser-349 by ULK1 promotes interaction with KEAP1 and inactivation of the BCR(KEAP1) complex, promoting NFE2L2/NRF2 nuclear accumulation and expression of phase II detoxifying enzymes. Phosphorylated in vitro by TTN. Ubiquitinated by UBE2J1 and RNF26 at Lys-435: ubiquitinated SQSTM1 attracts specific vesicle-associated adapters, forming a molecular bridge that restrains cognate vesicles in the perinuclear region and organizes the endosomal pathway for efficient cargo transport. Ubiquitination by UBE2D2 and UBE2D3 increases its ability to bind polyubiquitin chains by destabilizing the UBA dimer interface. Deubiquitination by USP15 releases target vesicles for fast transport into the cell periphery. Ubiquitinated by the BCR(KEAP1) complex at Lys-420, increasing SQSTM1 sequestering activity and promoting its degradation. Ubiquitinated via ‘Lys-29’ and ‘Lys-33’-linked polyubiquitination leading to xenophagic targeting of bacteria and inhibition of their replication. Acetylated at Lys-420 and Lys-435 by KAT5/TIP60, promotes activity by destabilizing the UBA dimer interface and increases binding affinity to ubiquitinated proteins. Deacetylated by HDAC6. Palmitoylation at Cys-289 and Cys-290 by ZDHHC19 is required for efficient autophagic degradation of SQSTM1-cargo complexes by promoting affinity for ATG8 proteins and recruitment of p62 bodies to autophagosomes. Dealmitoylated at Cys-289 and Cys-290 by LYPLA1. (Microbial infection) Cleaved by S.pyogenes SpeB protease; leading to its degradation. Degradation by SpeB prevents autophagy, promoting to S.pyogenes intracellular replication. (Microbial infection) Deubiquitinated by Epstein-Barr virus BPLF1; leading to inhibition of the recruitment of MAP1LC3A/LC3 to SQSTM1-positive structures.

Disease relevance. Paget disease of bone 3 (PDB3) [MIM:167250] A disorder of bone remodeling characterized by increased bone turnover affecting one or more sites throughout the skeleton, primarily the axial skeleton. Osteoclastic overactivity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone. The disease is caused by variants affecting the gene represented in this entry. In a cell model for Huntington disease (HD), appears to form a shell surrounding aggregates of mutant HTT that may protect cells from apoptosis, possibly by recruiting autophagosomal components to the polyubiquitinated protein aggregates. Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (FTDALS3) [MIM:616437] A neurodegenerative disorder characterized by frontotemporal dementia and/or amyotrophic lateral sclerosis in affected individuals. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. Some FTDALS3 patients may also develop Paget disease of bone. The disease is caused by variants affecting the gene represented in this entry. Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (NADGP) [MIM:617145] A neurodegenerative disorder characterized by gait abnormalities, ataxia, dysarthria, dystonia, vertical gaze palsy, and cognitive decline. Disease onset is in childhood or adolescence. NADGP transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry. Myopathy, distal, with rimmed vacuoles (DMRV) [MIM:617158] An autosomal dominant myopathy with adult onset, characterized by muscle weakness of the distal upper and lower limbs, walking difficulties, and proximal weakness of the shoulder girdle muscles. Muscle biopsy shows rimmed vacuoles. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving SQSTM1 is found in a form of acute lymphoblastic leukemia. Translocation t(5;9)(q35;q34) with NUP214.

Domain organisation. The UBA domain binds specifically ‘Lys-63’-linked polyubiquitin chains of polyubiquitinated substrates. Mediates the interaction with TRIM55. Both the UBA and PB1 domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies. The PB1 domain mediates homooligomerization and interactions with FHOD3, MAP2K5, NBR1, PRKCI, PRKCZ and WDR81. Both the PB1 and UBA domains are necessary and sufficient for the localization into the ubiquitin-containing inclusion bodies. The ZZ-type zinc finger mediates the interaction with RIPK1. The LIR (LC3-interacting region) motif mediates the interaction with ATG8 family proteins.

Induction. By proteasomal inhibitor PSI and prostaglandin J2 (PGJ2) (at protein level). By phorbol 12-myristate 13-acetate (PMA). Expression is directly activated by NFE2L2/NRF2; creating a positive feedback loop.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13501-1	1	yes
Q13501-2	2

RefSeq proteins (3): NP_001135770, NP_001135771, NP_003891* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000270	PB1_dom	Domain
IPR000433	Znf_ZZ	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR015940	UBA	Domain
IPR033741	SQSTM_UBA	Domain
IPR034866	PB1_p62	Domain
IPR043145	Znf_ZZ_sf	Homologous_superfamily
IPR052260	Autophagy_Rcpt_SigReg	Family
IPR053793	PB1-like	Domain

Pfam: PF00564, PF00569, PF16577

UniProt features (174 total): sequence variant 50, mutagenesis site 35, modified residue 25, strand 15, region of interest 10, binding site 8, helix 6, turn 4, compositionally biased region 4, cross-link 4, initiator methionine 2, short sequence motif 2, domain 2, lipid moiety-binding region 2, chain 1, sequence conflict 1, site 1, zinc finger region 1, splice variant 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
6MJ7	X-RAY DIFFRACTION	1.41
5YP7	X-RAY DIFFRACTION	1.42
5YP8	X-RAY DIFFRACTION	1.45
5YPH	X-RAY DIFFRACTION	1.63
9H1J	X-RAY DIFFRACTION	1.73
6MIU	X-RAY DIFFRACTION	1.9
5YPC	X-RAY DIFFRACTION	1.96
5YPG	X-RAY DIFFRACTION	2.2
7R1O	X-RAY DIFFRACTION	2.2
4MJS	X-RAY DIFFRACTION	2.5
5YPA	X-RAY DIFFRACTION	2.5
6KHZ	X-RAY DIFFRACTION	2.8
5YPE	X-RAY DIFFRACTION	2.85
5YPB	X-RAY DIFFRACTION	2.9
5YPF	X-RAY DIFFRACTION	2.95
6JM4	X-RAY DIFFRACTION	3.2
6TGY	ELECTRON MICROSCOPY	3.5
6TH3	ELECTRON MICROSCOPY	4
9HGE	ELECTRON MICROSCOPY	4.5
4UF9	ELECTRON MICROSCOPY	10.3
4UF8	ELECTRON MICROSCOPY	10.9
1Q02	SOLUTION NMR
2JY7	SOLUTION NMR
2JY8	SOLUTION NMR
2K0B	SOLUTION NMR
2KNV	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13501-F1	67.81	0.32

Antibody-complex structures (SAbDab): 1 — 9H1J

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 252–253 (breakpoint for translocation to form the nup214-sqstm1 fusion protein)

Ligand- & substrate-binding residues (8): 128; 131; 142; 145; 151; 154; 160; 163

Post-translational modifications (31): 2, 2, 24, 148, 170, 176, 207, 233, 249, 266, 269, 272, 282, 306, 328, 332, 349, 355, 361, 365 …

Mutagenesis-validated functional residues (35):

Position	Phenotype
7	loss of interactions with prkcz, prcki and nbr1. loss of dimerization; when associated with a-69.
9	no effect on interaction with lck.
13	no effect on interaction with prkci.
21–22	loss of interaction with prkci. alters dimerization.
67	no effect on interaction with prkcz.
69	no effect on interactions with prkcz, prkci and nbr1. loss of localization in cytoplasmic inclusion bodies. loss of dime
71	no effect on interaction with prkci.
73	no effect on interactions with prkcz and prkci.
80	no effect on interaction with prkci.
82	no effect on interaction with prkci.
289–290	abolished palmitoylation.
323–324	no effect on map1lc3b-binding.
332	no effect on map1lc3b-binding.
335–337	75% decrease in map1lc3b-binding.
338	strong decrease in map1lc3b-binding, disrupts interaction with gabarap.
342	no effect on map1lc3b-binding.
347	strongly decreased interaction with keap1.
349	impaired phosphorylation by ulk1, leading to decreased p62 body formation.
350	strongly decreased interaction with keap1.
351	strongly decreased interaction with keap1.
352	strongly decreased interaction with keap1.
398	no effect on polyubiquitin-binding.
403–407	mimics phosphorylation; increased phosphorylation at s-349.
403	abolished phosphorylation by ck2, leading to decreased affinity for ubiquitinated proteins. abolished ability to promote
403	mimmics phosphorylation; increased affinity for ubiquitinated proteins, leading to increased p62 body formation and auto

Function

Pathways and Gene Ontology

Reactome pathways

31 pathways

ID	Pathway
R-HSA-205043	NRIF signals cell death from the nucleus
R-HSA-209543	p75NTR recruits signalling complexes
R-HSA-209560	NF-kB is activated and signals survival
R-HSA-5205685	PINK1-PRKN Mediated Mitophagy
R-HSA-8951664	Neddylation
R-HSA-9020702	Interleukin-1 signaling
R-HSA-9664873	Pexophagy
R-HSA-9725370	Signaling by ALK fusions and activated point mutants
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9759194	Nuclear events mediated by NFE2L2
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1632852	Macroautophagy
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-193639	p75NTR signals via NF-kB
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-2262752	Cellular responses to stress
R-HSA-392499	Metabolism of proteins
R-HSA-446652	Interleukin-1 family signaling
R-HSA-449147	Signaling by Interleukins
R-HSA-5205647	Mitophagy
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-597592	Post-translational protein modification
R-HSA-73887	Death Receptor Signaling
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9612973	Autophagy
R-HSA-9663891	Selective autophagy
R-HSA-9700206	Signaling by ALK in cancer

MSigDB gene sets: 792 (showing top): SHEPARD_BMYB_MORPHOLINO_UP, AP1_01, GOBP_REGULATION_OF_AUTOPHAGY, FREAC2_01, GOBP_ENDOSOME_ORGANIZATION, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_VESICLE_ORGANIZATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, PID_IL1_PATHWAY, GOBP_REGULATION_OF_TOLL_LIKE_RECEPTOR_4_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_PROTEIN_TARGETING, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION

GO Biological Process (41): negative regulation of transcription by RNA polymerase II (GO:0000122), autophagy of mitochondrion (GO:0000422), mitophagy (GO:0000423), pexophagy (GO:0000425), temperature homeostasis (GO:0001659), immune system process (GO:0002376), response to ischemia (GO:0002931), transcription by RNA polymerase II (GO:0006366), ubiquitin-dependent protein catabolic process (GO:0006511), protein import into nucleus (GO:0006606), autophagy (GO:0006914), apoptotic process (GO:0006915), endosome organization (GO:0007032), intracellular protein localization (GO:0008104), positive regulation of autophagy (GO:0010508), regulation of mitochondrion organization (GO:0010821), endosomal transport (GO:0016197), macroautophagy (GO:0016236), cell differentiation (GO:0030154), protein catabolic process (GO:0030163), negative regulation of protein ubiquitination (GO:0031397), cellular response to stress (GO:0033554), negative regulation of toll-like receptor 4 signaling pathway (GO:0034144), intracellular signal transduction (GO:0035556), aggrephagy (GO:0035973), positive regulation of apoptotic process (GO:0043065), regulation of canonical NF-kappaB signal transduction (GO:0043122), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of Ras protein signal transduction (GO:0046578), regulation of protein complex stability (GO:0061635), brown fat cell proliferation (GO:0070342), protein targeting to vacuole involved in autophagy (GO:0071211), energy homeostasis (GO:0097009), response to mitochondrial depolarisation (GO:0098780), negative regulation of ferroptosis (GO:0110076), membraneless organelle assembly (GO:0140694), positive regulation of long-term synaptic potentiation (GO:1900273), positive regulation of protein localization to plasma membrane (GO:1903078), protein localization to perinuclear region of cytoplasm (GO:1905719), toll-like receptor 4 signaling pathway (GO:0034142)

GO Molecular Function (21): protein kinase C binding (GO:0005080), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674), receptor tyrosine kinase binding (GO:0030971), ubiquitin protein ligase binding (GO:0031625), ionotropic glutamate receptor binding (GO:0035255), signaling adaptor activity (GO:0035591), signaling receptor activity (GO:0038023), SH2 domain binding (GO:0042169), identical protein binding (GO:0042802), ubiquitin binding (GO:0043130), protein-containing complex binding (GO:0044877), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), ubiquitin-modified protein reader activity (GO:0140036), protein sequestering activity (GO:0140311), molecular sequestering activity (GO:0140313), molecular condensate scaffold activity (GO:0140693), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (25): phagophore assembly site (GO:0000407), P-body (GO:0000932), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), late endosome (GO:0005770), autophagosome (GO:0005776), endoplasmic reticulum (GO:0005783), cytosol (GO:0005829), inclusion body (GO:0016234), aggresome (GO:0016235), PML body (GO:0016605), sarcomere (GO:0030017), intracellular membraneless organelle (GO:0043232), amphisome (GO:0044753), autolysosome (GO:0044754), extracellular exosome (GO:0070062), sperm midpiece (GO:0097225), Lewy body (GO:0097413), glutamatergic synapse (GO:0098978), nucleus (GO:0005634), lysosome (GO:0005764), endosome (GO:0005768), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
p75NTR signals via NF-kB	2
p75 NTR receptor-mediated signalling	2
Cell death signalling via NRAGE, NRIF and NADE	1
Mitophagy	1
Post-translational protein modification	1
Interleukin-1 family signaling	1
Selective autophagy	1
Signaling by ALK in cancer	1
Cellular response to chemical stress	1
KEAP1-NFE2L2 pathway	1
Immune System	1
Autophagy	1
Death Receptor Signaling	1
Cellular responses to stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	4
cytoplasm	4
autophagy	3
intracellular anatomical structure	3
macroautophagy	2
protein-macromolecule adaptor activity	2
binding	2
intracellular membrane-bounded organelle	2
inclusion body	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
autophagy of mitochondrion	1
autophagy of peroxisome	1
multicellular organismal-level homeostasis	1
biological_process	1
response to stress	1
DNA-templated transcription	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
endomembrane system organization	1
vesicle organization	1
macromolecule localization	1
positive regulation of catabolic process	1
regulation of autophagy	1
mitochondrion organization	1
regulation of organelle organization	1
vesicle-mediated transport	1
intracellular transport	1

Protein interactions and networks

STRING

4302 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SQSTM1	MAP1LC3B	Q9GZQ8	999
SQSTM1	GABARAPL2	P60520	997
SQSTM1	F5GZY7	F5GZY7	997
SQSTM1	GABARAP	O95166	996
SQSTM1	KEAP1	Q14145	995
SQSTM1	MAP1A	P78559	994
SQSTM1	TRAF6	Q9Y4K3	992
SQSTM1	OPTN	Q96CV9	991
SQSTM1	NBR1	Q14596	985
SQSTM1	CD300C	Q08708	981
SQSTM1	LCK	P06239	979
SQSTM1	ATG5	Q9H1Y0	974
SQSTM1	MAP1S	Q66K74	973
SQSTM1	CALCOCO2	Q13137	973
SQSTM1	WDFY3	Q8IZQ1	972

IntAct

574 interactions, top by confidence:

A	B	Type	Score
MAP1LC3B	SQSTM1	psi-mi:“MI:0407”(direct interaction)	0.980
SQSTM1	MAP1LC3B	psi-mi:“MI:0915”(physical association)	0.980
MAP1LC3B	SQSTM1	psi-mi:“MI:0914”(association)	0.980
SQSTM1	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.970
SQSTM1	KEAP1	psi-mi:“MI:0915”(physical association)	0.970
GABARAPL2	SQSTM1	psi-mi:“MI:0915”(physical association)	0.970
KEAP1	SQSTM1	psi-mi:“MI:0915”(physical association)	0.970
GABARAPL2	SQSTM1	psi-mi:“MI:0914”(association)	0.970
KEAP1	SQSTM1	psi-mi:“MI:0407”(direct interaction)	0.970
SQSTM1	GABARAPL1	psi-mi:“MI:0915”(physical association)	0.950
GABARAP	SQSTM1	psi-mi:“MI:0914”(association)	0.950
SQSTM1	MAP1LC3A	psi-mi:“MI:0915”(physical association)	0.950
GABARAP	SQSTM1	psi-mi:“MI:0915”(physical association)	0.950
MAP1LC3C	SQSTM1	psi-mi:“MI:0914”(association)	0.900
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
PRKCZ	PRKCI	psi-mi:“MI:0914”(association)	0.890
SQSTM1	SQSTM1	psi-mi:“MI:0915”(physical association)	0.890

BioGRID (2393): SQSTM1 (Two-hybrid), SQSTM1 (Two-hybrid), SQSTM1 (Affinity Capture-Western), SQSTM1 (Affinity Capture-Western), SQSTM1 (Reconstituted Complex), MAP1LC3A (Co-crystal Structure), MAP1LC3A (Reconstituted Complex), SQSTM1 (Affinity Capture-Western), UBC (Affinity Capture-Western), UBC (Reconstituted Complex), BCL2 (Reconstituted Complex), SQSTM1 (Affinity Capture-Western), tat (Reconstituted Complex), SQSTM1 (Two-hybrid), KEAP1 (Two-hybrid)

ESM2 similar proteins: A1YFY1, A2AH22, A2T6X5, A3KPW9, A4IH17, A5D9M6, A7X5R6, E7FAG6, O35445, P46379, Q09463, Q0II22, Q13501, Q15011, Q1W1Y5, Q3KPV4, Q3V209, Q4V9Y1, Q56B11, Q5M807, Q5PRF9, Q5R5B0, Q5RBA5, Q64337, Q6DIP3, Q6MG49, Q6MGB6, Q6P135, Q6PA26, Q6PC78, Q80XS6, Q8BIG4, Q8IZL8, Q8LPN7, Q8WMN5, Q91YL2, Q99942, Q9BV68, Q9C0C7, Q9D0C1

Diamond homologs: O08623, O95714, P14199, Q13501, Q14596, Q24629, Q4U2R1, Q501R9, Q5RBA5, Q5RC94, Q64337, Q68LP1, Q8R516, Q96AX9, Q9P792, O60941, O70585, P34664, P84060, Q0KI50, Q6GNY1, Q7YU29, Q804S5, Q80SY4, Q86YT6, Q9D2N4, Q9VDW3, Q9VDW6, Q9VUX2, Q9Y048, Q9Y4J8, M1BJF6, P97432, Q9SB64, Q5ZIJ9, Q3TT38, A2CI98, Q1LZE1, Q6GPB6, Q7T321

SIGNOR signaling

31 interactions.

A	Effect	B	Mechanism
GABARAPL1	“up-regulates activity”	SQSTM1	binding
GABARAPL2	“up-regulates activity”	SQSTM1	binding
MAP1LC3A	up-regulates	SQSTM1	binding
MAP1LC3B	up-regulates	SQSTM1	binding
CDK1	up-regulates	SQSTM1	phosphorylation
NBR1	up-regulates	SQSTM1	binding
TBK1	up-regulates	SQSTM1	phosphorylation
CyclinB/CDK1	up-regulates	SQSTM1	phosphorylation
PEX5	“up-regulates activity”	SQSTM1	binding
SQSTM1	“up-regulates quantity”	WDFY3	binding
USP15	“down-regulates activity”	SQSTM1	deubiquitination
RNF26	“up-regulates activity”	SQSTM1	ubiquitination
BNIP1	“up-regulates activity”	SQSTM1	binding
FBXO3	“down-regulates quantity by destabilization”	SQSTM1	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	SQSTM1	polyubiquitination
EGFR	“down-regulates activity”	SQSTM1	phosphorylation
ULK1	“down-regulates quantity by destabilization”	SQSTM1	phosphorylation
PRKN	“down-regulates quantity by destabilization”	SQSTM1	ubiquitination
TRIM21	“down-regulates activity”	SQSTM1	ubiquitination
NEDD4	“down-regulates quantity by destabilization”	SQSTM1	ubiquitination
MAP3K3	“up-regulates activity”	SQSTM1	phosphorylation
MELK	“up-regulates activity”	SQSTM1	phosphorylation
SQSTM1	“down-regulates quantity by destabilization”	KEAP1	ubiquitination
PRKCD	“up-regulates activity”	SQSTM1	phosphorylation
SQSTM1	“down-regulates quantity by destabilization”	SOD1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Macroautophagy	9	13.8×	1e-05
Cellular response to chemical stress	7	13.3×	2e-04
KEAP1-NFE2L2 pathway	8	12.8×	6e-05
Autophagy	5	9.9×	6e-03
Clathrin-mediated endocytosis	6	6.8×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitophagy	9	31.1×	4e-09
insulin-like growth factor receptor signaling pathway	5	26.9×	2e-04
autophagosome assembly	10	24.4×	4e-09
autophagosome maturation	6	22.9×	6e-05
extrinsic apoptotic signaling pathway via death domain receptors	5	21.8×	4e-04
macroautophagy	6	15.7×	3e-04
obsolete positive regulation of NF-kappaB transcription factor activity	7	15.6×	7e-05
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	5	11.4×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

870 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	39
Likely pathogenic	14
Uncertain significance	434
Likely benign	271
Benign	46

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071292	NM_003900.5(SQSTM1):c.1210A>G (p.Met404Val)	Pathogenic
1076912	NM_003900.5(SQSTM1):c.244G>T (p.Glu82Ter)	Pathogenic
1323651	NM_003900.5(SQSTM1):c.415del (p.Arg139fs)	Pathogenic
1334783	NM_003900.5(SQSTM1):c.301+2T>A	Pathogenic
1334784	NM_003900.5(SQSTM1):c.934_936delinsTGA (p.Arg312Ter)	Pathogenic
1334785	NM_003900.5(SQSTM1):c.875_876insT (p.Ser294fs)	Pathogenic
1459183	NM_003900.5(SQSTM1):c.1165G>C (p.Glu389Gln)	Pathogenic
1691078	NM_003900.5(SQSTM1):c.784_820del (p.Gly262fs)	Pathogenic
1704477	NM_003900.5(SQSTM1):c.1135_1138del (p.Glu379fs)	Pathogenic
1912117	NM_003900.5(SQSTM1):c.815_818del (p.Val271_Ser272insTer)	Pathogenic
1948518	NM_003900.5(SQSTM1):c.259_260insATGCCTTTTCCAGTGACGAGGAATTGACGAGGAAT (p.Met87fs)	Pathogenic
1962648	NM_003900.5(SQSTM1):c.979dup (p.Glu327fs)	Pathogenic
202210	NM_003900.5(SQSTM1):c.1132A>T (p.Lys378Ter)	Pathogenic
2083476	NM_003900.5(SQSTM1):c.820G>T (p.Glu274Ter)	Pathogenic
2136359	NM_003900.5(SQSTM1):c.1175del (p.Pro392fs)	Pathogenic
2166073	NM_003900.5(SQSTM1):c.901G>T (p.Glu301Ter)	Pathogenic
265780	NM_003900.5(SQSTM1):c.2T>A (p.Met1Lys)	Pathogenic
265781	NM_003900.5(SQSTM1):c.311_312del (p.Glu104fs)	Pathogenic
265782	NM_003900.5(SQSTM1):c.286C>T (p.Arg96Ter)	Pathogenic
2943392	NM_003900.5(SQSTM1):c.1111C>T (p.Gln371Ter)	Pathogenic
2948186	NM_003900.5(SQSTM1):c.763dup (p.Val255fs)	Pathogenic
2949509	NM_003900.5(SQSTM1):c.973C>T (p.Gln325Ter)	Pathogenic
2952106	NM_003900.5(SQSTM1):c.309dup (p.Glu104fs)	Pathogenic
3750300	NM_003900.5(SQSTM1):c.571G>T (p.Gly191Ter)	Pathogenic
3753178	NM_003900.5(SQSTM1):c.616_617del (p.Trp206fs)	Pathogenic
3757914	NM_003900.5(SQSTM1):c.686C>A (p.Ser229Ter)	Pathogenic
4292363	NM_003900.5(SQSTM1):c.106G>T (p.Glu36Ter)	Pathogenic
451357	NM_003900.5(SQSTM1):c.823_824del (p.Ser275fs)	Pathogenic
4759223	NM_003900.5(SQSTM1):c.1149C>G (p.Tyr383Ter)	Pathogenic
4783866	NM_003900.5(SQSTM1):c.838G>T (p.Glu280Ter)	Pathogenic

SpliceAI

1597 predictions. Top by Δscore:

Variant	Effect	Δscore
5:179822950:C:G	acceptor_gain	1.0000
5:179822951:A:AG	acceptor_gain	1.0000
5:179822952:A:G	acceptor_gain	1.0000
5:179822954:CTA:C	acceptor_loss	1.0000
5:179822956:A:AG	acceptor_gain	1.0000
5:179822957:G:GA	acceptor_gain	1.0000
5:179822957:GA:G	acceptor_gain	1.0000
5:179822957:GAT:G	acceptor_gain	1.0000
5:179822957:GATGA:G	acceptor_gain	1.0000
5:179823050:AAAGG:A	donor_loss	1.0000
5:179823052:AG:A	donor_gain	1.0000
5:179823052:AGGT:A	donor_loss	1.0000
5:179823053:GG:G	donor_gain	1.0000
5:179823053:GGTAA:G	donor_loss	1.0000
5:179823054:G:GG	donor_gain	1.0000
5:179823054:GTAAG:G	donor_loss	1.0000
5:179823853:T:TA	acceptor_gain	1.0000
5:179823856:A:AG	acceptor_gain	1.0000
5:179823856:A:G	acceptor_loss	1.0000
5:179823857:G:A	acceptor_loss	1.0000
5:179823857:G:GA	acceptor_gain	1.0000
5:179823857:GA:G	acceptor_gain	1.0000
5:179823857:GAGA:G	acceptor_gain	1.0000
5:179823857:GAGAA:G	acceptor_gain	1.0000
5:179824086:AGGT:A	donor_loss	1.0000
5:179824088:GT:G	donor_loss	1.0000
5:179824089:T:G	donor_loss	1.0000
5:179824180:A:AT	acceptor_loss	1.0000
5:179824180:AG:A	acceptor_gain	1.0000
5:179824181:GG:G	acceptor_gain	1.0000

AlphaMissense

2874 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:179823938:T:C	C128R	1.000
5:179823938:T:A	C128S	0.999
5:179823939:G:A	C128Y	0.999
5:179823939:G:C	C128S	0.999
5:179823940:C:G	C128W	0.999
5:179823980:T:C	C142R	0.999
5:179823989:T:C	C145R	0.999
5:179824007:T:C	C151R	0.999
5:179825215:T:A	L248H	0.999
5:179836463:T:C	L398P	0.999
5:179836472:T:G	M401R	0.999
5:179836486:T:C	F406L	0.999
5:179836487:T:C	F406S	0.999
5:179836488:C:A	F406L	0.999
5:179836488:C:G	F406L	0.999
5:179836508:T:A	L413H	0.999
5:179836508:T:C	L413P	0.999
5:179836517:T:C	L416P	0.999
5:179836520:T:C	L417P	0.999
5:179836550:C:A	A427D	0.999
5:179836553:T:C	L428P	0.999
5:179820957:G:C	K7N	0.998
5:179820957:G:T	K7N	0.998
5:179822976:T:A	V75D	0.998
5:179822982:T:C	F77S	0.998
5:179823939:G:T	C128F	0.998
5:179823947:T:A	C131S	0.998
5:179823948:G:C	C131S	0.998
5:179824009:T:G	C151W	0.998
5:179824016:T:A	C154S	0.998

dbSNP variants (sampled 300 via entrez): RS1000117387 (5:179834341 T>C), RS1000140030 (5:179823669 G>A,T), RS1000170620 (5:179808338 AG>A), RS1000365167 (5:179808583 C>T), RS1000419685 (5:179813467 A>G), RS1000699365 (5:179807616 C>T), RS1000721803 (5:179820284 A>C,G), RS1000748158 (5:179816055 G>A), RS1000750225 (5:179807707 C>T), RS1000791733 (5:179814787 G>C), RS1000834877 (5:179819789 C>A,T), RS1000896465 (5:179813068 A>G), RS1001054875 (5:179805010 T>G), RS1001057049 (5:179836087 C>CATCA), RS1001136807 (5:179819553 C>T)

Disease associations

OMIM: gene MIM:601530 | disease phenotypes: MIM:105550, MIM:602080, MIM:617145, MIM:616437, MIM:167250, MIM:617158

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset	Definitive	Autosomal recessive
osteosarcoma	Strong	Autosomal dominant
Paget disease of bone 3	Strong	Autosomal dominant
frontotemporal dementia and/or amyotrophic lateral sclerosis 3	Strong	Autosomal dominant
behavioral variant of frontotemporal dementia	Supportive	Autosomal dominant
frontotemporal dementia with motor neuron disease	Supportive	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 3	Moderate	AD

Mondo (13): frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (MONDO:0007105), Paget disease of bone 2, early-onset (MONDO:0011183), neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (MONDO:0014940), frontotemporal dementia and/or amyotrophic lateral sclerosis 3 (MONDO:0014640), Paget disease of bone 3 (MONDO:0008176), myopathy, distal, with rimmed vacuoles (MONDO:0014945), SQSTM1-related multisystem proteinopathy (MONDO:0800464), amyotrophic lateral sclerosis (MONDO:0004976), bone Paget disease (MONDO:0005382), spastic paraplegia-Paget disease of bone syndrome (MONDO:0018005), osteosarcoma (MONDO:0009807), behavioral variant of frontotemporal dementia (MONDO:0017160), frontotemporal dementia with motor neuron disease (MONDO:0017161)

Orphanet (5): Frontotemporal dementia with motor neuron disease (Orphanet:275872), Behavioral variant of frontotemporal dementia (Orphanet:275864), Amyotrophic lateral sclerosis (Orphanet:803), Spastic paraplegia-Paget disease of bone syndrome (Orphanet:329475), NON RARE IN EUROPE: Paget disease of bone (Orphanet:280110)

HPO phenotypes

149 total (30 of 149 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000217	Xerostomia
HP:0000365	Hearing impairment
HP:0000474	Thickened nuchal skin fold
HP:0000508	Ptosis
HP:0000511	Vertical supranuclear gaze palsy
HP:0000605	Supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000710	Hyperorality
HP:0000711	Restlessness
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000719	Inappropriate behavior
HP:0000723	Restrictive behavior
HP:0000733	Motor stereotypy
HP:0000734	Disinhibition
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000751	Personality changes
HP:0000757	Lack of insight
HP:0000815	Hypergonadotropic hypogonadism
HP:0001251	Ataxia

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002245_23	Alzheimer’s disease (late onset)	7.000000e-07
GCST90002394_34	Monocyte percentage of white cells	8.000000e-31
GCST90002399_435	Neutrophil percentage of white cells	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D012516	Osteosarcoma	C04.557.450.565.575.650; C04.557.450.795.620
C566288	Frontotemporal Dementia With Motor Neuron Disease (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (7): CHEMBL4106129 (PROTEIN-PROTEIN INTERACTION), CHEMBL4295816 (SINGLE PROTEIN), CHEMBL6066859 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066860 (PROTEIN-PROTEIN INTERACTION), CHEMBL6066861 (PROTEIN-PROTEIN INTERACTION), CHEMBL6177909 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193767 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10277	MRNIP, SQSTM1		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Autophagy receptors

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
oroxylin A	Inhibition	5.88	pKd

ChEMBL bioactivities

14 potent at pChembl≥5 of 14 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.82	IC50	150	nM	CHEMBL3962296
6.75	IC50	180	nM	CHEMBL3925906
6.72	IC50	190	nM	CHEMBL3928944
6.64	IC50	230	nM	CHEMBL3906697
6.62	Kd	241.7	nM	CHEMBL5653589
6.59	ED50	257.6	nM	CHEMBL5653589
6.43	IC50	370	nM	CHEMBL3953535
6.04	IC50	910	nM	CHEMBL2402207
6.00	IC50	1000	nM	CHEMBL3934789
5.85	IC50	1400	nM	CHEMBL3939457
5.83	Kd	1490	nM	CHEMBL5183436
5.82	IC50	1500	nM	CHEMBL3948237
5.62	IC50	2400	nM	CHEMBL3977467

PubChem BioAssay actives

13 with measured affinity, of 26 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-[1,4-bis[(4-ethoxyphenyl)sulfonylamino]naphthalen-2-yl]butanoic acid	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	0.1500	uM
2-[1,4-bis[(4-ethoxyphenyl)sulfonylamino]naphthalen-2-yl]sulfanylacetic acid	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	0.1800	uM
3-[1,4-bis[(4-ethoxyphenyl)sulfonylamino]naphthalen-2-yl]propanoic acid	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	0.1900	uM
2-[1,4-bis[(4-ethoxyphenyl)sulfonylamino]naphthalen-2-yl]acetic acid	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	0.2300	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149479: Binding affinity to human SQSTM1 incubated for 45 mins by Kinobead based pull down assay	kd	0.2417	uM
methyl 2-[1,4-bis[(4-ethoxyphenyl)sulfonylamino]naphthalen-2-yl]sulfanylacetate	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	0.3700	uM
4-methoxy-N-[4-[(4-methoxyphenyl)sulfonylamino]naphthalen-1-yl]benzenesulfonamide	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	0.9100	uM
4-ethoxy-N-[4-[(4-ethoxyphenyl)sulfonylamino]-3-(1H-1,2,4-triazol-5-ylsulfanyl)naphthalen-1-yl]benzenesulfonamide	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	1.0000	uM
4-ethoxy-N-[4-[(4-ethoxyphenyl)sulfonylamino]naphthalen-1-yl]benzenesulfonamide	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	1.4000	uM
6-[1-(3,4,5-trimethoxyphenyl)triazol-4-yl]quinazoline-2,4-diamine	1848866: Binding affinity to P62 (unknown origin) by MST assay	kd	1.4900	uM
4-ethoxy-N-[4-[(4-ethoxyphenyl)sulfonylamino]-3-(2-oxopropyl)naphthalen-1-yl]benzenesulfonamide	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	1.5000	uM
4-methoxy-N-[4-[(4-methoxyphenyl)sulfonylamino]-3-(2-oxopropyl)naphthalen-1-yl]benzenesulfonamide	1331148: Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization assay	ic50	2.4000	uM

CTD chemical–gene interactions

475 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Chloroquine	affects cotreatment, increases expression, decreases expression, decreases reaction, increases abundance (+3 more)	43
sodium arsenite	affects expression, increases abundance, increases reaction, increases phosphorylation, affects response to substance (+14 more)	32
3-methyladenine	affects reaction, affects cotreatment, decreases reaction, decreases expression, increases reaction (+4 more)	30
bafilomycin A1	affects cotreatment, decreases reaction, increases expression, increases reaction, affects binding (+4 more)	24
Sirolimus	increases reaction, increases degradation, affects cotreatment, increases expression, decreases expression (+1 more)	18
Acetylcysteine	decreases reaction, increases expression, increases degradation, increases reaction, affects cotreatment (+5 more)	17
Arsenic Trioxide	increases reaction, increases localization, increases expression, affects reaction, decreases expression (+7 more)	16
Cisplatin	decreases response to substance, increases expression, affects cotreatment, affects expression, affects reaction (+2 more)	14
Arsenic	increases expression, decreases methylation, decreases reaction, increases abundance, increases reaction (+9 more)	11
Cadmium Chloride	affects reaction, increases reaction, increases expression, decreases expression, decreases reaction (+1 more)	9
Particulate Matter	decreases reaction, increases expression, decreases expression, increases abundance, affects expression (+1 more)	9
bisphenol A	decreases expression, decreases reaction, affects expression, affects cotreatment, increases expression	8
Cadmium	increases expression, decreases expression, decreases reaction, increases abundance, affects reaction (+2 more)	8
Tobacco Smoke Pollution	increases expression	8
Benzo(a)pyrene	affects methylation, increases expression	7
Paraquat	decreases expression, increases expression, affects cotreatment, decreases reaction, increases reaction (+3 more)	7
Cyclosporine	affects cotreatment, increases expression, decreases expression, decreases reaction	7
Ammonium Chloride	decreases reaction, increases expression, affects cotreatment, decreases expression, affects reaction	6
Doxorubicin	decreases reaction, increases degradation, decreases expression, increases expression	6
Rotenone	decreases reaction, increases expression, decreases expression, increases reaction, decreases response to substance	6
Palmitic Acid	increases reaction, affects cotreatment, decreases reaction, increases abundance, decreases expression (+1 more)	6
arsenite	increases expression, increases phosphorylation, decreases expression, increases abundance, decreases reaction (+1 more)	5
bafilomycin A	affects cotreatment, affects expression, decreases expression, decreases reaction, increases expression	5
4-phenylbutyric acid	decreases expression, decreases reaction, increases expression	5
pyrazolanthrone	decreases expression, decreases reaction, affects binding, increases reaction, increases expression (+2 more)	5
dorsomorphin	decreases expression, decreases reaction, increases reaction, increases expression, affects cotreatment	5
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases degradation, increases expression (+1 more)	5
Acrolein	decreases expression, decreases reaction, affects cotreatment, increases expression, increases abundance	5
Vehicle Emissions	decreases reaction, increases abundance, increases expression, affects reaction, affects expression (+1 more)	5
Hydrogen Peroxide	affects expression, affects binding, increases reaction, increases expression, decreases response to substance	5

ChEMBL screening assays

20 unique, capped per target: 20 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3870928	Binding	Inhibition of recombinant GST-His-tagged Keap1-DC domain (321 to 609 residues) (unknown origin) expressed in Escherichia coli/FAM-labeled phosphorylated p62 (unknown origin) interaction measured after 30 mins by fluorescence polarization as	Synthesis of Keap1-phosphorylated p62 and Keap1-Nrf2 protein-protein interaction inhibitors and their inhibitory activity. — Bioorg Med Chem Lett

Cellosaurus cell lines

23 cell lines: 19 cancer cell line, 3 transformed cell line, 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6LP	U2OS SQSTM1 KO	Cancer cell line	Female
CVCL_B1E7	Abcam HCT 116 SQSTM1 KO	Cancer cell line	Male
CVCL_B3I3	Abcam HEK293T SQSTM1 KO	Transformed cell line	Female
CVCL_C2VN	HeLa S3 penta KO	Cancer cell line	Female
CVCL_C2VP	HeLa S3 penta KO-ATG13 KO	Cancer cell line	Female
CVCL_C2VQ	HeLa S3 penta KO-ATG14 KO	Cancer cell line	Female
CVCL_C2VR	HeLa S3 penta KO-TBK1 KO	Cancer cell line	Female
CVCL_C2VS	HeLa S3 penta KO-ULK1/ULK2 DKO	Cancer cell line	Female
CVCL_C2VT	HeLa S3 penta KO-TBK1/ULK1/ULK2 TKO	Cancer cell line	Female
CVCL_C8QB	HeLa S3 penta KO-AZI2/TBKBP1 DKO clone 20	Cancer cell line	Female

Clinical trials (associated diseases)

600 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01669369	PHASE4	UNKNOWN	Clinical Trial of Lithium Carbonate Combined With Neo-adjuvant Chemotherapy to Treat Osteosarcoma
NCT04854018	PHASE4	COMPLETED	Indo-cyanine Green (ICG) in Paediatric Oncology MIS
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00001217	PHASE3	COMPLETED	Osteosarcoma Study #2: A Randomized Trial of Pre-Surgical Chemotherapy vs. Immediate Surgery and Adjuvant Chemotherapy in the Treatment of Non-Metastatic Osteosarcoma. A Pediatric Oncology Group Phase III Study
NCT00134030	PHASE3	COMPLETED	Combination Chemotherapy, PEG-Interferon Alfa-2b, and Surgery in Treating Patients With Osteosarcoma
NCT00180908	PHASE3	COMPLETED	Comparison of High-Dose Methotrexate (HDM) Plus Doxorubicin to HDM Plus Etoposide-Ifosfamide in Osteosarcoma Children
NCT01176981	PHASE3	COMPLETED	Outpatient Administration of High Dose Methotrexate (HD MTX) in Patients With Osteosarcoma
NCT01987596	PHASE3	TERMINATED	Study of Fixed vs. Flexible Filgrastim to Accelerate Bone Marrow Recovery After Chemotherapy in Children With Cancer
NCT05024253	PHASE3	COMPLETED	Perioperative Use of Tranexamic (TXA) in Bone Tumor Surgery Will Change in Blood Loss and Transfusion Requirements.
NCT05235165	PHASE3	RECRUITING	Thoracotomy Versus Thoracoscopic Management of Pulmonary Metastases in Patients With Osteosarcoma
NCT05328258	PHASE3	RECRUITING	Use of GnRHa During Chemotherapy for Fertility Protection
NCT06935409	PHASE3	ACTIVE_NOT_RECRUITING	Study of HS-20093 Versus Gemcitabine in Combination With Docetaxel in Treatment of Osteosarcoma After Previous Second-line Treatment Failure
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients