PPT1

Summary

PPT1 (palmitoyl-protein thioesterase 1, HGNC:9325) is a protein-coding gene on chromosome 1p34.2, encoding Palmitoyl-protein thioesterase 1 (P50897). Has thioesterase activity against fatty acid thioesters with 14 -18 carbons, including palmitoyl-CoA, S-palmitoyl-N-acetylcysteamine, and palmitoylated proteins.

The protein encoded by this gene is a small glycoprotein involved in the catabolism of lipid-modified proteins during lysosomal degradation. The encoded enzyme removes thioester-linked fatty acyl groups such as palmitate from cysteine residues. Defects in this gene are a cause of infantile neuronal ceroid lipofuscinosis 1 (CLN1, or INCL) and neuronal ceroid lipofuscinosis 4 (CLN4). Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5538 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 777 total — 71 pathogenic, 85 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9325
Approved symbol	PPT1
Name	palmitoyl-protein thioesterase 1
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Aliases	CLN1, INCL
Ensembl gene	ENSG00000131238
Ensembl biotype	protein_coding
OMIM	600722
Entrez	5538

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 protein_coding, 7 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000372775, ENST00000372779, ENST00000433473, ENST00000439754, ENST00000449045, ENST00000526547, ENST00000527311, ENST00000529905, ENST00000530076, ENST00000530704, ENST00000641083, ENST00000641236, ENST00000641319, ENST00000641381, ENST00000641471, ENST00000641548, ENST00000641691, ENST00000641924, ENST00000642050, ENST00000917762

RefSeq mRNA: 3 — MANE Select: NM_000310 NM_000310, NM_001142604, NM_001363695

CCDS: CCDS44119, CCDS447, CCDS85955

Canonical transcript exons

ENST00000642050 — 9 exons

Exon	Start	End
ENSE00000899698	40092045	40092172
ENSE00001670667	40097115	40097252
ENSE00003548333	40092398	40092507
ENSE00003582374	40080397	40080487
ENSE00003609646	40089410	40089512
ENSE00003644974	40076842	40076913
ENSE00003684915	40091329	40091399
ENSE00003790611	40078560	40078658
ENSE00003814062	40072712	40074183

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 98.6963 / max 2602.2682, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11898	98.6963	1828

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.17	gold quality
mononuclear cell	CL:0000842	99.15	gold quality
leukocyte	CL:0000738	99.11	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.68	gold quality
pigmented layer of retina	UBERON:0001782	98.63	gold quality
lateral globus pallidus	UBERON:0002476	98.53	gold quality
pons	UBERON:0000988	98.52	gold quality
granulocyte	CL:0000094	98.47	gold quality
parotid gland	UBERON:0001831	98.40	gold quality
substantia nigra pars compacta	UBERON:0001965	98.38	gold quality
adult organism	UBERON:0007023	98.36	gold quality
blood	UBERON:0000178	98.30	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.27	gold quality
islet of Langerhans	UBERON:0000006	98.23	gold quality
mammary duct	UBERON:0001765	98.16	gold quality
trabecular bone tissue	UBERON:0002483	98.13	gold quality
choroid plexus epithelium	UBERON:0003911	98.13	gold quality
skin of hip	UBERON:0001554	98.09	gold quality
superior vestibular nucleus	UBERON:0007227	98.09	gold quality
subthalamic nucleus	UBERON:0001906	98.04	gold quality
inferior vagus X ganglion	UBERON:0005363	98.04	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.93	gold quality
superficial temporal artery	UBERON:0001614	97.92	gold quality
spleen	UBERON:0002106	97.82	gold quality
ventral tegmental area	UBERON:0002691	97.82	gold quality
medulla oblongata	UBERON:0001896	97.75	gold quality
lower lobe of lung	UBERON:0008949	97.73	gold quality
epithelium of mammary gland	UBERON:0003244	97.60	gold quality
parietal lobe	UBERON:0001872	97.55	gold quality
synovial joint	UBERON:0002217	97.55	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	68.30
E-HCAD-1	yes	51.65
E-MTAB-10553	yes	34.96
E-HCAD-13	yes	23.60
E-MTAB-6701	yes	22.85
E-MTAB-6678	yes	22.77
E-CURD-112	yes	14.53
E-MTAB-8410	yes	13.40
E-MTAB-10042	yes	8.68
E-CURD-88	yes	8.59
E-MTAB-9801	yes	7.86
E-MTAB-7606	no	916.39
E-MTAB-3929	no	913.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting PPT1, 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-6077	99.99	68.04	2299
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-2116-3P	99.74	64.32	889
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-3682-3P	99.58	67.63	865
HSA-MIR-4696	99.48	67.48	1040
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-125A-5P	99.36	70.59	1640
HSA-MIR-125B-5P	99.36	70.36	1662
HSA-MIR-548V	99.29	69.47	1157
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-4999-3P	99.11	65.55	424

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 28)

• mutated in neuronal ceroid lipofuscinosis (PMID:12025857)
• The clinical, biochemical, and molecular genetic aspects of lysosomal storage disorders are discussed in this review (PMID:12125808)
• The crystal structure of palmitoyl protein thioesterase-2 (PPT2) reveals the basis for divergent substrate specificities of the two lysosomal thioesterases, PPT1 and PPT2. (PMID:12855696)
• there is a close correlation between CLN2 and CLN1 expression and colorectal carcinoma progression and metastasis and suggest that they may be potential molecular targets (PMID:16518810)
• Results show that PPT1-deficiency causes a defect in fluid-phase and receptor-mediated endocytosis. (PMID:16542649)
• ER stress due to PPT1-deficiency increases ROS and disrupts calcium homeostasis activating caspase-9 and caspase-9 activation mediates caspase-3 activation and apoptosis contributing to rapid neurodegeneration in INCL. (PMID:16571600)
• Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1. (PMID:17261688)
• Palmitoyl protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve terminals in humans and mice (PMID:18704195)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• study presents clinical and diagnostic investigations in six children with variant late infantile neuronal ceroid lipofuscinosis and mutations in CLN1 including a new large-scale deletion on one allele (PMID:19302939)
• Results describe the correlation between the three-dimensional structural changes in mutant palmitoyl protein thioesterase 1 and biochemical phenotypes. (PMID:19793631)
• Stop codon read-through with PTC124 induces palmitoyl-protein thioesterase-1 activity, reduces thioester load and suppresses apoptosis in cultured cells from Infantile neuronal ceroid lipofuscinosis patients. (PMID:21704547)
• This neuroimaging finding in PPT1-related neuronal ceroid lipofuscinosis was not previously reported. (PMID:22520356)
• Data suggest that human monocytes and macrophages express PPT1; PPT1 appears to contribute 32-40% of 2-arachidonylglycerol hydrolysis activity in THP1 monocyte cell line. (PMID:24083319)
• Data (including data from knockout mice) suggest that deficiency of PPT1 leads to accumulation of granular osmiophilic deposits in many cell types, especially in astrocytes. [review-like article] (PMID:25233404)
• analysis of the palmitoyl protein thioesterase 1 interactome in SH-SY5Y human neuroblastoma cells (PMID:25865307)
• we reveal the existence of a positive feedback loop, where palmitoylation of PPT1 results in decreased activity and subsequent elevation in the amount of palmitoylated proteins. (PMID:26731412)
• Proteomics analysis on isolated cilia revealed 660 proteins, which differed in their abundance levels between wild type and Ppt1 knock out. (PMID:28334871)
• Targeting PPT1 blocks mTOR signaling in a manner distinct from catalytic inhibitors, while concurrently inhibiting autophagy, thereby providing a new strategy for cancer therapy. (PMID:28899863)
• the combination of elevated glycolysis and deficient MRPL13 activity was closely linked to CLN1-mediated tumor activity in human hepatoma cells (PMID:28978646)
• The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development. (PMID:29631617)
• High PPT1 expression is associated with cancer. (PMID:30442709)
• the study contributes four novel variants to the spectrum of PPT1 gene mutations and eight novel variants to the TPP1 gene mutation data in neuronal ceroid lipofuscinoses type I and type II (PMID:30541466)
• Human INCL fibroblasts display abnormal mitochondrial and lysosomal networks and heightened susceptibility to ROS-induced cell death. (PMID:33561134)
• Computational and structural investigation of Palmitoyl-Protein Thioesterase 1 (PPT1) protein causing Neuronal Ceroid Lipofuscinoses (NCL). (PMID:36088080)
• Identification of PPT1 as a lysosomal core gene with prognostic value in hepatocellular carcinoma. (PMID:37103469)
• PPT1 Promotes Growth and Inhibits Ferroptosis of Oral Squamous Cell Carcinoma Cells. (PMID:38299399)
• The function of PPT1 is to hydrolyze long-chain fatty acids from cysteine residues of fatty acylated proteins in the lysosome. (PMID:8816748)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppt1	ENSDARG00000039980
mus_musculus	Ppt1	ENSMUSG00000028657
mus_musculus		ENSMUSG00000134847
rattus_norvegicus	Ppt1	ENSRNOG00000012616
drosophila_melanogaster	Ppt1	FBGN0030057
caenorhabditis_elegans		WBGENE00004092

Paralogs (2): DOLPP1 (ENSG00000167130), PPT2 (ENSG00000221988)

Protein

Protein identifiers

Palmitoyl-protein thioesterase 1 — P50897 (reviewed: P50897)

Alternative names: Palmitoyl-protein hydrolase 1

All UniProt accessions (14): A0A286YEP3, A0A286YF39, A0A286YFE3, A0A286YFF7, A0A286YFL6, A0A286YFL8, A0A2C9F2P4, E9PIA8, E9PK48, E9PMG2, E9PP28, E9PSE5, P50897, Q5T0S4

UniProt curated annotations — full annotation on UniProt →

Function. Has thioesterase activity against fatty acid thioesters with 14 -18 carbons, including palmitoyl-CoA, S-palmitoyl-N-acetylcysteamine, and palmitoylated proteins. In contrast to PPT2, PPT1 can hydrolyze palmitoylated proteins and palmitoylcysteine.

Subunit / interactions. Interacts with CLN5. Interacts with ATP5F1A and ATP5F1B.

Subcellular location. Lysosome. Secreted. Golgi apparatus. Endoplasmic reticulum.

Post-translational modifications. Glycosylated.

Disease relevance. Ceroid lipofuscinosis, neuronal, 1 (CLN1) [MIM:256730] A form of neuronal ceroid lipofuscinosis with variable age at onset. Infantile, late-infantile, juvenile, and adult onset have been reported. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The lipopigment pattern seen most often in CLN1 is referred to as granular osmiophilic deposits (GROD). The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Palmitoylation reduces PPT1 enzymatic activity.

Similarity. Belongs to the palmitoyl-protein thioesterase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P50897-1	1	yes
P50897-2	2

RefSeq proteins (3): NP_000301, NP_001136076, NP_001350624 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002472	Palm_thioest	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily

Pfam: PF02089

Enzyme classification (BRENDA):

• EC 3.1.2.2 — palmitoyl-CoA hydrolase (BRENDA: 40 organisms, 184 substrates, 159 inhibitors, 142 Km, 46 kcat entries)
• EC 3.1.2.22 — palmitoyl[protein] hydrolase (BRENDA: 9 organisms, 80 substrates, 16 inhibitors, 7 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

39 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HEXADECANOYL-COA	—	26
DODECANOYL-COA	0.0018–0.325	12
LAUROYL-COA	0.0385–0.185	10
OLEOYL-COA	0.0014–0.0088	8
TETRADECANOYL-COA	0.0016–0.024	8
ARACHIDONOYL-COA	0.0004–0.0092	6
DECANOYL-COA	0.0027–0.067	6
P-NITROPHENYL BUTYRATE	0.61–1.88	6
PALMITOLEOYL-COA	0.0014–0.058	6
N-CARBOBENZOXY-L-TYROSINE P-NITROPHENYL ESTER	0.043–0.174	5
OCTADECANOYL-COA	0.0004–0.034	5
OCTANOYL-COA	0.007–0.118	5
EICOSANOYL-COA	0.0004–0.0048	3
HEXANOYL-COA	0.0055–0.077	3
PALMITOYL-COA	0.0033–0.023	3

Catalyzed reactions (Rhea), 4 shown:

• hexadecanoyl-CoA + H2O = hexadecanoate + CoA + H(+) (RHEA:16645)
• S-hexadecanoyl-L-cysteinyl-[protein] + H2O = L-cysteinyl-[protein] + hexadecanoate + H(+) (RHEA:19233)
• S-hexadecanoyl-N-acetylcysteamine + H2O = N-acetylcysteamine + hexadecanoate + H(+) (RHEA:84099)
• S-hexadecanoyl-N-acetylcysteine methyl ester + H2O = N-acetylcysteine methyl ester + hexadecanoate + H(+) (RHEA:84103)

UniProt features (68 total): sequence variant 24, helix 17, strand 12, disulfide bond 3, active site 3, glycosylation site 3, signal peptide 1, chain 1, splice variant 1, mutagenesis site 1, turn 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3GRO	X-RAY DIFFRACTION	2.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50897-F1	92.05	0.83

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 (3): 115; 233; 289

Post-translational modifications (1): 6

Disulfide bonds (3): 96–128, 152–160, 45–46

Glycosylation sites (3): 197, 212, 232

Mutagenesis-validated functional residues (1):

Position	Phenotype
6	does not affect its subcellular localizations. increases depalmitoylation activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-75105	Fatty acyl-CoA biosynthesis

MSigDB gene sets: 457 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, ZHAN_LATE_DIFFERENTIATION_GENES_UP, GOBP_PINOCYTOSIS, GOBP_COGNITION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_BEHAVIOR, GOBP_VACUOLE_ORGANIZATION, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOCC_VACUOLAR_MEMBRANE, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_ADULT_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH

GO Biological Process (29): protein depalmitoylation (GO:0002084), endocytosis (GO:0006897), receptor-mediated endocytosis (GO:0006898), pinocytosis (GO:0006907), lysosomal lumen acidification (GO:0007042), neurotransmitter secretion (GO:0007269), nervous system development (GO:0007399), brain development (GO:0007420), visual perception (GO:0007601), grooming behavior (GO:0007625), associative learning (GO:0008306), adult locomotory behavior (GO:0008344), protein transport (GO:0015031), lipid catabolic process (GO:0016042), sphingolipid catabolic process (GO:0030149), protein catabolic process (GO:0030163), negative regulation of cell growth (GO:0030308), membrane raft organization (GO:0031579), negative regulation of toll-like receptor 9 signaling pathway (GO:0034164), negative regulation of apoptotic process (GO:0043066), negative regulation of neuron apoptotic process (GO:0043524), fatty-acyl-CoA biosynthetic process (GO:0046949), positive regulation of receptor-mediated endocytosis (GO:0048260), positive regulation of pinocytosis (GO:0048549), neuron development (GO:0048666), regulation of synapse structure or activity (GO:0050803), lysosome organization (GO:0007040), toll-like receptor 9 signaling pathway (GO:0034162), macromolecule depalmitoylation (GO:0098734)

GO Molecular Function (8): palmitoyl-(protein) hydrolase activity (GO:0008474), phospholipase A2 inhibitor activity (GO:0019834), lysophosphatidic acid binding (GO:0035727), long-chain fatty acyl-CoA hydrolase activity (GO:0052816), sulfatide binding (GO:0120146), protein binding (GO:0005515), hydrolase activity (GO:0016787), palmitoyl hydrolase activity (GO:0098599)

GO Cellular Component (18): extracellular region (GO:0005576), nucleus (GO:0005634), lysosome (GO:0005764), lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), cytosol (GO:0005829), synaptic vesicle (GO:0008021), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), synaptic vesicle membrane (GO:0030672), neuronal cell body (GO:0043025), lysosomal lumen (GO:0043202), membrane raft (GO:0045121), extracellular exosome (GO:0070062), presynaptic cytosol (GO:0099523), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Fatty acid metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
presynapse	3
cellular anatomical structure	3
intracellular membrane-bounded organelle	3
cytoplasm	3
macromolecule depalmitoylation	2
endocytosis	2
lysosome	2
endomembrane system	2
neuron projection	2
protein deacylation	1
lipoprotein catabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
vacuolar acidification	1
neurotransmitter transport	1
chemical synaptic transmission	1
establishment of localization in cell	1
signal release from synapse	1
system development	1
central nervous system development	1
animal organ development	1
head development	1
sensory perception of light stimulus	1
behavior	1
learning	1
locomotory behavior	1
adult behavior	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
lipid metabolic process	1
catabolic process	1
sphingolipid metabolic process	1
lipid catabolic process	1
macromolecule catabolic process	1
protein metabolic process	1
regulation of cell growth	1
cell growth	1

Protein interactions and networks

STRING

2078 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPT1	CLN3	Q13286	985
PPT1	CLN5	O75503	978
PPT1	CLN6	Q9NWW5	977
PPT1	CLN8	Q9UBY8	970
PPT1	TPP1	O14773	957
PPT1	DNAJC5	Q9H3Z4	915
PPT1	MFSD8	Q8NHS3	915
PPT1	KCTD7	Q96MP8	897
PPT1	FLI1	Q01543	834
PPT1	CTSD	P07339	829
PPT1	CLCN6	P51797	762
PPT1	UBAC1	Q9BSL1	696
PPT1	CCNL2	Q96S94	685
PPT1	SNAP25	P13795	673
PPT1	LYPLA1	O75608	656
PPT1	CDK1	P06493	656

IntAct

67 interactions, top by confidence:

A	B	Type	Score
ACRV1	PPT1	psi-mi:“MI:0915”(physical association)	0.560
PIAS1	PPT1	psi-mi:“MI:0915”(physical association)	0.560
	PPT1	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	PPT1	psi-mi:“MI:0915”(physical association)	0.560
ATL1	PPT1	psi-mi:“MI:0915”(physical association)	0.560
ASB3	PPT1	psi-mi:“MI:0915”(physical association)	0.560
PLEKHG7	PPT1	psi-mi:“MI:0915”(physical association)	0.560
ZNF829	PPT1	psi-mi:“MI:0915”(physical association)	0.560
ORF10	PPT1	psi-mi:“MI:0914”(association)	0.530
ORF38	PPT1	psi-mi:“MI:0915”(physical association)	0.500
ORF38	PPT1	psi-mi:“MI:0914”(association)	0.500
PPT1	MICB	psi-mi:“MI:0915”(physical association)	0.400
GNAQ	PPT1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (299): VCP (Affinity Capture-MS), DBT (Affinity Capture-MS), MAP1B (Affinity Capture-MS), VAPB (Affinity Capture-MS), ATP1A1 (Affinity Capture-MS), PRDX1 (Affinity Capture-MS), SLC25A1 (Affinity Capture-MS), ATP5B (Affinity Capture-MS), CRMP1 (Affinity Capture-MS), DLAT (Affinity Capture-MS), CRIP2 (Affinity Capture-MS), ATP5A1 (Affinity Capture-MS), DBH (Affinity Capture-MS), VGF (Affinity Capture-MS), PRDX2 (Affinity Capture-MS)

ESM2 similar proteins: O00469, O18823, O35298, O35448, O65355, O70489, O80731, O88531, O97860, P10619, P13686, P16675, P28039, P29288, P45478, P45479, P50897, P70158, Q05117, Q1JQA0, Q20390, Q3ZC91, Q5HZX7, Q5R748, Q641Z7, Q66GM8, Q67ZU1, Q6DBP4, Q6GNY7, Q6PCJ9, Q811A3, Q84JS1, Q8H5F8, Q8HXW6, Q920A5, Q920A6, Q92484, Q93V61, Q95KC9, Q99ML5

Diamond homologs: B0CM95, B0KWE9, B1MTH4, B2KI79, O59747, O88531, P45478, P45479, P50897, P53223, Q20390, Q86IX2, Q86YN1, Q8HXW6, Q9C2M6, Q9JMF7, Q9W3C7, O35448, Q54CM0, Q1JQA0, O70489, Q6GNY7, Q9UMR5, Q9VKH6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	71
Likely pathogenic	85
Uncertain significance	227
Likely benign	278
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1067368	NM_000310.4(PPT1):c.628-2A>G	Pathogenic
1069555	NM_000310.4(PPT1):c.712_713del (p.Pro238fs)	Pathogenic
1070722	NC_000001.10:g.(?_40557947)_40561572del	Pathogenic
1071260	NM_000310.4(PPT1):c.614_620del (p.Ile205fs)	Pathogenic
1073044	NM_000310.4(PPT1):c.263del (p.Val88fs)	Pathogenic
1074230	NM_000310.4(PPT1):c.51G>A (p.Trp17Ter)	Pathogenic
1076529	NM_000310.4(PPT1):c.343_344dup (p.Gln116fs)	Pathogenic
1385000	NM_000310.4(PPT1):c.728G>A (p.Trp243Ter)	Pathogenic
1388947	NM_000310.4(PPT1):c.741C>A (p.Tyr247Ter)	Pathogenic
1389507	NM_000310.4(PPT1):c.2T>A (p.Met1Lys)	Pathogenic
1454858	NC_000001.10:g.(?40558060)(40561460_?)del	Pathogenic
188857	NM_000310.4(PPT1):c.541G>A (p.Val181Met)	Pathogenic
2011017	NM_000310.4(PPT1):c.722C>A (p.Ser241Ter)	Pathogenic
2022496	NM_000310.4(PPT1):c.775C>T (p.Gln259Ter)	Pathogenic
2027871	NM_000310.4(PPT1):c.112del (p.Trp38fs)	Pathogenic
2035352	NM_000310.4(PPT1):c.1A>C (p.Met1Leu)	Pathogenic
2035598	NM_000310.4(PPT1):c.21_25dup (p.Leu9fs)	Pathogenic
206642	NM_000310.4(PPT1):c.234+1G>A	Pathogenic
2110798	NM_000310.4(PPT1):c.440_441del (p.Phe147fs)	Pathogenic
2132906	NM_000310.4(PPT1):c.72_73delinsTT (p.Gln25Ter)	Pathogenic
236410	NM_000310.4(PPT1):c.532del (p.Glu178fs)	Pathogenic
2422850	NC_000001.10:g.(?40542494)(40562910_?)del	Pathogenic
2422851	NC_000001.10:g.(?40555072)(40558194_?)del	Pathogenic
2422854	NC_000001.10:g.(?40561110)(40562920_?)del	Pathogenic
2702053	NM_000310.4(PPT1):c.319C>T (p.Gln107Ter)	Pathogenic
2735090	NM_000310.4(PPT1):c.125-2A>T	Pathogenic
2744463	NM_000310.4(PPT1):c.820del (p.Met274fs)	Pathogenic
2752503	NM_000310.4(PPT1):c.169del (p.Met57fs)	Pathogenic
2764049	NM_000310.4(PPT1):c.628-2A>T	Pathogenic
2779960	NM_000310.4(PPT1):c.316C>T (p.Gln106Ter)	Pathogenic

SpliceAI

1132 predictions. Top by Δscore:

Variant	Effect	Δscore
1:40074181:GTCCT:G	acceptor_loss	1.0000
1:40074182:TCCT:T	acceptor_loss	1.0000
1:40074183:CCT:C	acceptor_loss	1.0000
1:40076909:AACCA:A	acceptor_gain	1.0000
1:40076910:ACCA:A	acceptor_gain	1.0000
1:40076911:CCA:C	acceptor_gain	1.0000
1:40076911:CCAC:C	acceptor_gain	1.0000
1:40076912:CA:C	acceptor_gain	1.0000
1:40076912:CAC:C	acceptor_gain	1.0000
1:40076913:ACTG:A	acceptor_loss	1.0000
1:40076914:C:CC	acceptor_gain	1.0000
1:40078554:TCTCA:T	donor_loss	1.0000
1:40078555:CTCA:C	donor_loss	1.0000
1:40078556:TCA:T	donor_loss	1.0000
1:40078557:CA:C	donor_loss	1.0000
1:40078558:A:C	donor_loss	1.0000
1:40078559:C:A	donor_loss	1.0000
1:40078561:T:TA	donor_gain	1.0000
1:40080391:GCTT:G	donor_loss	1.0000
1:40080392:CTTAC:C	donor_loss	1.0000
1:40080394:TA:T	donor_loss	1.0000
1:40080394:TAC:T	donor_gain	1.0000
1:40080395:A:AC	donor_gain	1.0000
1:40080395:AC:A	donor_gain	1.0000
1:40080396:C:CC	donor_gain	1.0000
1:40080396:CC:C	donor_gain	1.0000
1:40080396:CCCG:C	donor_gain	1.0000
1:40080483:CGAGG:C	acceptor_gain	1.0000
1:40080484:GAGG:G	acceptor_gain	1.0000
1:40080485:AGG:A	acceptor_gain	1.0000

AlphaMissense

2010 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40091355:A:G	L136P	0.995
1:40078596:G:C	F230L	0.994
1:40078596:G:T	F230L	0.994
1:40078598:A:G	F230L	0.994
1:40076908:A:C	F244L	0.993
1:40076908:A:T	F244L	0.993
1:40076910:A:G	F244L	0.993
1:40080466:C:A	W186C	0.993
1:40080466:C:G	W186C	0.993
1:40092158:G:C	S83R	0.993
1:40092158:G:T	S83R	0.993
1:40092160:T:G	S83R	0.993
1:40074115:A:C	H289Q	0.992
1:40074115:A:T	H289Q	0.992
1:40076902:A:C	F246L	0.992
1:40076902:A:T	F246L	0.992
1:40076904:A:G	F246L	0.992
1:40078564:G:C	S241W	0.992
1:40080468:A:G	W186R	0.992
1:40080468:A:T	W186R	0.992
1:40091396:C:A	R122S	0.992
1:40091396:C:G	R122S	0.992
1:40097127:A:G	W38R	0.992
1:40097127:A:T	W38R	0.992
1:40091329:C:G	G145R	0.991
1:40078589:C:G	D233H	0.990
1:40080427:G:C	S199R	0.990
1:40080427:G:T	S199R	0.990
1:40080429:T:G	S199R	0.990
1:40092076:C:G	A111P	0.990

dbSNP variants (sampled 300 via entrez): RS1000100510 (1:40075650 T>C), RS1000390025 (1:40072890 C>T), RS1000494425 (1:40098801 T>C), RS1000820488 (1:40084115 A>C), RS1000904542 (1:40077360 C>T), RS1000984476 (1:40080663 C>T), RS1001099496 (1:40093137 G>A), RS1001102516 (1:40074287 T>A,C), RS1001257903 (1:40088107 G>C), RS1001329528 (1:40096015 C>T), RS1001333349 (1:40080909 C>A,G), RS1001432113 (1:40090081 G>A), RS1001497100 (1:40074588 C>T), RS1001636663 (1:40093718 C>G), RS1001733682 (1:40078528 T>A,C)

Disease associations

OMIM: gene MIM:600722 | disease phenotypes: MIM:214200, MIM:256730, MIM:117000, MIM:268000, MIM:617755, MIM:108600

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis 1	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	AR

Mondo (8): neuronal ceroid lipofuscinosis 1 (MONDO:0009744), central core myopathy (MONDO:0007294), neuronal ceroid lipofuscinosis (MONDO:0016295), retinitis pigmentosa (MONDO:0019200), intellectual disability (MONDO:0001071), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596), congenital nervous system disorder (MONDO:0002320), spastic ataxia (MONDO:0017845)

Orphanet (8): CLN1 disease (Orphanet:228329), Central core disease (Orphanet:597), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Retinitis pigmentosa (Orphanet:791), BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482), Spastic ataxia (Orphanet:316226), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000253	Progressive microcephaly
HP:0000529	Progressive visual loss
HP:0000546	Retinal degeneration
HP:0000550	Undetectable electroretinogram
HP:0000608	Macular degeneration
HP:0000618	Blindness
HP:0000648	Optic atrophy
HP:0000654	Decreased light- and dark-adapted electroretinogram amplitude
HP:0000716	Depression
HP:0000737	Irritability
HP:0000738	Hallucinations
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001336	Myoclonus
HP:0001371	Flexion contracture
HP:0001922	Vacuolated lymphocytes
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002059	Cerebral atrophy
HP:0002074	Increased neuronal autofluorescent lipopigment
HP:0002353	EEG abnormality
HP:0002360	Sleep disturbance
HP:0002361	Psychomotor deterioration
HP:0002371	Loss of speech
HP:0003621	Juvenile onset

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_1801	Blood protein levels	1.000000e-79
GCST90002402_542	Platelet count	2.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020512	Myopathy, Central Core	C05.651.575.300; C10.668.491.550.300
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2331051 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — 3.1.-.- Ester bond enzymes

ChEMBL bioactivities

2 potent at pChembl≥5 of 6 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.70	IC50	2000	nM	CHEMBL2332876
5.00	IC50	1e+04	nM	CHEMBL2332875

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 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
(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S,3S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-3-(hexadecanoylamino)-2-[[2-[3-[(4-nitro-2,1,3-benzoxadiazol-7-yl)amino]propanoylamino]acetyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]hexanoyl]amino]-3-methylpentanoyl]amino]hexanoyl]amino]hexanoic acid	731120: Inhibition of PPT1 in human fibroblast/lymphoblast cell lysate using fluorescent-based MUGSP as substrate after 1 to 3 hrs	ic50	2.0000	uM
(2S)-2-[[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-acetamidoacetyl)amino]-3-(hexadecanoylamino)propanoyl]amino]-3-methylbutanoyl]amino]-6-aminohexanoyl]amino]-3-methylpentanoyl]amino]-6-aminohexanoyl]amino]-6-aminohexanoic acid	731121: Inhibition of PPT1 (unknown origin) in cell lysates using fluorescent-based MUGSP as substrate after 1 to 3 hrs	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, decreases expression, increases abundance, increases oxidation, affects expression	3
Ozone	decreases expression, increases oxidation, increases abundance, affects expression, affects cotreatment	3
bisphenol A	decreases expression, increases expression	2
methacrylaldehyde	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Benzo(a)pyrene	affects methylation, increases expression	2
Valproic Acid	increases expression, decreases expression	2
Cyclosporine	decreases expression	2
Cadmium Chloride	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
3,19-(2-bromobenzylidene)andrographolide	decreases response to substance, increases expression	1
beauvericin	affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
glycidyl methacrylate	decreases expression	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects expression	1
cobaltous chloride	decreases expression	1
sulindac sulfide	decreases expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
enniatins	affects cotreatment, decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2344831	Binding	Induction of PPT1 T75P/R151X mutant activity in lymphoblast derived from patients at 10 uM after 72 hrs relative to control	Pharmacological chaperones as therapeutics for lysosomal storage diseases. — J Med Chem

Cellosaurus cell lines

20 cell lines: 12 transformed cell line, 4 cancer cell line, 2 induced pluripotent stem cell, 1 finite cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C7KZ	HT146B	Induced pluripotent stem cell	Male
CVCL_C7L0	HT146F	Induced pluripotent stem cell	Male
CVCL_D5F5	HeLa::TMEM192-3xHA PPT1 KO	Cancer cell line	Female
CVCL_DA35	GM16080	Transformed cell line	Male
CVCL_DA36	GM16081	Transformed cell line	Female
CVCL_DA37	GM16082	Transformed cell line	Female
CVCL_DA38	GM16083	Transformed cell line	Female
CVCL_DA39	GM16084	Transformed cell line	Male
CVCL_DA40	GM16085	Transformed cell line	Female
CVCL_DA41	GM16106	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa