TPP1

Summary

TPP1 (tripeptidyl peptidase 1, HGNC:2073) is a protein-coding gene on chromosome 11p15.4, encoding Tripeptidyl-peptidase 1 (O14773). Lysosomal serine protease with tripeptidyl-peptidase I activity.

This gene encodes a member of the sedolisin family of serine proteases. The protease functions in the lysosome to cleave N-terminal tripeptides from substrates, and has weaker endopeptidase activity. It is synthesized as a catalytically-inactive enzyme which is activated and auto-proteolyzed upon acidification. Mutations in this gene result in late-infantile neuronal ceroid lipofuscinosis, which is associated with the failure to degrade specific neuropeptides and a subunit of ATP synthase in the lysosome.

Source: NCBI Gene 1200 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronal ceroid lipofuscinosis (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 1,278 total — 98 pathogenic, 83 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_000391

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2073
Approved symbol	TPP1
Name	tripeptidyl peptidase 1
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	LPIC, TPP-1
Ensembl gene	ENSG00000166340
Ensembl biotype	protein_coding
OMIM	607998
Entrez	1200

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 17 protein_coding, 16 retained_intron, 7 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000299427, ENST00000428886, ENST00000436873, ENST00000524611, ENST00000524788, ENST00000524903, ENST00000524924, ENST00000528571, ENST00000528657, ENST00000528807, ENST00000528917, ENST00000530040, ENST00000531754, ENST00000533371, ENST00000534644, ENST00000642892, ENST00000643342, ENST00000643439, ENST00000643479, ENST00000643516, ENST00000644151, ENST00000644218, ENST00000644683, ENST00000644810, ENST00000644831, ENST00000644933, ENST00000645020, ENST00000645285, ENST00000645331, ENST00000645620, ENST00000646691, ENST00000646777, ENST00000647016, ENST00000647152, ENST00000647209, ENST00000647346, ENST00000682424, ENST00000895468, ENST00000895469, ENST00000895470, ENST00000895471, ENST00000931962

RefSeq mRNA: 1 — MANE Select: NM_000391 NM_000391

CCDS: CCDS7770

Canonical transcript exons

ENST00000299427 — 13 exons

Exon	Start	End
ENSE00001102236	6616315	6616503
ENSE00001102249	6615171	6615329
ENSE00001102252	6616005	6616074
ENSE00001348942	6619384	6619422
ENSE00001826904	6612768	6614686
ENSE00003483995	6617301	6617428
ENSE00003578517	6617626	6617776
ENSE00003589176	6616661	6616859
ENSE00003624610	6616975	6617153
ENSE00003636553	6619196	6619267
ENSE00003637165	6614866	6614991
ENSE00003643573	6618776	6618915
ENSE00003689508	6615442	6615562

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.1604 / max 975.9358, expressed in 1823 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118455	73.0295	1823
118454	0.1308	36

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	99.35	gold quality
retina	UBERON:0000966	99.33	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.10	gold quality
inferior olivary complex	UBERON:0002127	98.85	gold quality
right adrenal gland cortex	UBERON:0035827	98.80	gold quality
germinal epithelium of ovary	UBERON:0001304	98.77	gold quality
right adrenal gland	UBERON:0001233	98.64	gold quality
visceral pleura	UBERON:0002401	98.64	gold quality
stromal cell of endometrium	CL:0002255	98.56	gold quality
left adrenal gland	UBERON:0001234	98.51	gold quality
spleen	UBERON:0002106	98.47	gold quality
parietal pleura	UBERON:0002400	98.40	gold quality
leukocyte	CL:0000738	98.37	gold quality
pleura	UBERON:0000977	98.36	gold quality
adrenal cortex	UBERON:0001235	98.36	gold quality
monocyte	CL:0000576	98.33	gold quality
mononuclear cell	CL:0000842	98.33	gold quality
left adrenal gland cortex	UBERON:0035825	98.31	gold quality
trabecular bone tissue	UBERON:0002483	98.23	gold quality
olfactory bulb	UBERON:0002264	98.16	gold quality
granulocyte	CL:0000094	98.13	gold quality
lymph node	UBERON:0000029	97.97	gold quality
vermiform appendix	UBERON:0001154	97.89	gold quality
type B pancreatic cell	CL:0000169	97.82	gold quality
gall bladder	UBERON:0002110	97.79	gold quality
smooth muscle tissue	UBERON:0001135	97.75	gold quality
adrenal gland	UBERON:0002369	97.69	gold quality
bone marrow cell	CL:0002092	97.61	gold quality
placenta	UBERON:0001987	97.60	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.47	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	44.15
E-MTAB-6678	yes	40.05
E-MTAB-8142	yes	18.31
E-HCAD-9	yes	16.16
E-MTAB-9801	yes	3.46
E-MTAB-7606	no	2138.11
E-MTAB-6386	no	609.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting TPP1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4500	99.99	72.72	2367
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-2110	99.96	66.68	1930
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809

Literature-anchored findings (GeneRIF, showing 40)

• The clinical, biochemical, and molecular genetic aspects of lysosomal storage disorders are discussed in this review (PMID:12125808)
• Data show that three neuronal ceroid lipofuscinoses disease forms with similar tissue pathology are connected at the molecular level: CLN5 polypeptides directly interact with the CLN2 and CLN3 proteins (PMID:12134079)
• Missense mutations, R127Q, N286S, and T353P represent novel, previously not described alleles. (PMID:12376936)
• human tripeptidyl-peptidase I is processed by a serine protease to the mature, active form in vivo (PMID:12488460)
• a novel mutation in neuronal ceroid lipofuscinosis (PMID:12698559)
• CLN2 gene mutations may result in low cerebrospinal fluid pterin production in classical neuronal ceroid lipofuscinoses of late infantile onset. (PMID:12950156)
• human tripeptidyl-peptidase I must be N-glycosylated for folding, trafficking, and stability (PMID:14702339)
• mutant Asn286Ser CLN2 lacks one oligosaccharide chain resulting in enzymatic inactivation (PMID:14736728)
• intramolecular (unimolecular) mechanism of TPP I activation and autoprocessing (PMID:15143070)
• TPP-I is the predominant proteolytic enzyme responsible for the intracellular degradation of neuromedin B (PMID:15158442)
• Functional analyses of CLN2 mutations reveal transport disruption of tripeptidyl-peptidase I to lysosomes. (PMID:15317752)
• tripeptidyl-peptidase I activation, activity, and stability are regulated by glycosaminoglycans (PMID:15582991)
• Ser475 and Asp360, also Glu272, Asp276, and Asp327 are important for catalytic activity of tripeptidyl peptidase I (PMID:15733845)
• Substrate-binding cleft of TPP-I composed of only 6 subsites; TPP-I prefers bulky and hydrophobic amino acid residues at P(1) position and Ala, Arg, or Asp at P(2) position; hydrophilic interactions at the S(2) subsite are necessary for TPP-I. (PMID:16091586)
• Mutational screening of CLCN2 gene, revealed a homozygous mutation G2003C (exon 17), leading to a Ser/Thr substitution at the codon 668, in two of the three in malignant migrating partial seizures patients. (PMID:16168594)
• 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)
• Clinical features, histological findings, and genetic study reveal that CLN2 type is the most common form of neuronal ceroid lipofuscinosis. There is male predominance of 90.1% in this part of the Arab world. (PMID:17690061)
• CLN2/TPP1 deficiency: the novel mutation IVS7-10A>G causes intron retention and is associated with a mild disease phenotype. (PMID:17959406)
• the tripeptidyl peptidase I prosegment is a potent, slow-binding inhibitor of its cognate enzyme (PMID:18411270)
• Lysosome-related genes, such as CLN2, CLN3, and HEXB, may be involved in the pathogenesis of adipose tissue hypertrophy in TED. (PMID:18552385)
• Structure of tripeptidyl-peptidase I provides insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis. (PMID:19038966)
• Crystal structure and autoactivation pathway of the precursor form of human tripeptidyl-peptidase 1, the enzyme deficient in late infantile ceroid lipofuscinosis (PMID:19038967)
• genetic deletion of the lysosomal serine protease CLN2 and the subsequent loss of its catalytic function confer resistance to TNF in non-neuronal somatic cells in a Bid-dependent manner, indicating that CLN2 plays a role in TNF-induced cell death (PMID:19246452)
• This novel deletion mutation in the CLN2 gene in a family of Arab origin from Israel sheds further light on the epidemiology of neuronal ceroid lipofuscinosis as a worldwide disease (PMID:19748052)
• Data show that most TPPI variants displayed obstructed transport to the lysosomes. (PMID:20340139)
• The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2(CU)hCLN2). (PMID:20672930)
• the critical residues in the TPPI catalysis and its structure-function analysis (PMID:20689811)
• Intrathecal human tripeptidyl-peptidase 1 administration reduces lysosomal storage in a canine model of late infantile neuronal ceroid lipofuscinosis. (PMID:21784683)
• Studies indicate that TPP-I is the only member of the sedolisin family that has been shown to exhibit tripeptidyl peptidase activity and is related to the fatal hereditary disease, Batten disease. (PMID:22016395)
• This study demonistrated that the CLN2 gene 4 mutation in late infantile neuronal ceroid lipofuscinosis. (PMID:22832778)
• Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor alpha and may have implications in late infantile Batten disease therapy (PMID:22989886)
• To our knowledge, our results bring the first evidence of a mechanism that links TPP-1 deficiency and oxidative stress-induced changes in mitochondrial morphology. (PMID:23249249)
• The variant juvenile phenotype comprises approximately 50% of CLN2 in South America. The five most frequent South American mutations comprise 66% of pathological alleles. (PMID:23266810)
• hypothesize that loss of function variants abolishing TPP1 enzyme activity lead to CLN2 disease, whereas variants that diminish TPP1 enzyme activity lead to SCAR7 (PMID:23418007)
• TPP1 mutants utilize the advantages of a zebrafish model for understanding the pathogenesis of late infantile (or classic late infantile neuronal ceroid lipofuscinosis) disease. (PMID:23587805)
• TPP1(CLN2) mutation is associated with neuronal ceroid lipofuscinosis. (PMID:24271013)
• To confirm clinical suspicion of CLN2 disease, the recommended gold standard for laboratory diagnosis is demonstration of deficient TPP1 enzyme activity (in leukocytes, fibroblasts, or dried blood spots) and the identification of causative mutations in each allele of the TPP1/CLN2 gene. (PMID:27553878)
• TPP1 is overexpressed in hepatocellular carcinoma tissues and significantly correlated with poor prognosis of hepatocellular carcinoma patients.RFX5 acts as a direct positive transcriptional regulator of TPP1 in hepatocellular carcinoma. (PMID:27840983)
• These studies indicate that optimal treatment outcomes for CLN2 disease may require delivery of TPP1 systemically as well as directly to the central nervous system. (PMID:28079862)
• The reports the crystal structure of the N-terminal domain of TIN2 in complex with TIN2-binding motifs from TPP1 and TRF2, revealing how TIN2 interacts cooperatively with TPP1 and TRF2. (PMID:29160297)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tpp1	ENSDARG00000042793
mus_musculus	Tpp1	ENSMUSG00000030894
rattus_norvegicus	Tpp1	ENSRNOG00000019212

Protein

Protein identifiers

Tripeptidyl-peptidase 1 — O14773 (reviewed: O14773)

Alternative names: Cell growth-inhibiting gene 1 protein, Lysosomal pepstatin-insensitive protease, Tripeptidyl aminopeptidase, Tripeptidyl-peptidase I

All UniProt accessions (14): A0A2R8Y6T9, A0A2R8Y7I4, A0A2R8Y7U1, A0A2R8YCK4, A0A2R8YD45, A0A2R8YD72, A0A2R8YDY1, A0A2R8YE64, A0A2R8YGD1, A0A804HJ17, E7EV34, O14773, E9PME9, E9PPA4

UniProt curated annotations — full annotation on UniProt →

Function. Lysosomal serine protease with tripeptidyl-peptidase I activity. May act as a non-specific lysosomal peptidase which generates tripeptides from the breakdown products produced by lysosomal proteinases. Requires substrates with an unsubstituted N-terminus.

Subunit / interactions. Monomer. Interacts with CLN5. Interacts with CLN3.

Subcellular location. Lysosome. Melanosome.

Tissue specificity. Detected in all tissues examined with highest levels in heart and placenta and relatively similar levels in other tissues.

Post-translational modifications. Activated by autocatalytic proteolytical processing upon acidification. N-glycosylation is required for processing and activity.

Disease relevance. Ceroid lipofuscinosis, neuronal, 2 (CLN2) [MIM:204500] A form of neuronal ceroid lipofuscinosis. 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 CLN2 consists of curvilinear profiles. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia, autosomal recessive, 7 (SCAR7) [MIM:609270] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR7 patients show difficulty walking and writing, dysarthria, limb ataxia, and cerebellar atrophy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by diisopropyl fluorophosphate (DFP).

Cofactor. Binds 1 Ca(2+) ion per subunit.

Isoforms (2)

UniProt ID	Names	Canonical?
O14773-1	1	yes
O14773-2	2

RefSeq proteins (1): NP_000382* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000209	Peptidase_S8/S53_dom	Domain
IPR015366	S53_propep	Domain
IPR030400	Sedolisin_dom	Domain
IPR036852	Peptidase_S8/S53_dom_sf	Homologous_superfamily
IPR050819	Tripeptidyl-peptidase_I	Family

Pfam: PF00082, PF09286

Enzyme classification (BRENDA):

• EC 3.4.14.9 — tripeptidyl-peptidase I (BRENDA: 9 organisms, 97 substrates, 68 inhibitors, 32 Km, 32 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ALA-ALA-PHE-7-AMIDO-4-METHYLCOUMARIN	0.076–0.73	9
ALA-ARG-PHE-P-NITROPHENYLALANYL-ARG-LEU	0.004–0.123	2
ALA-ALA-PHE-4-NITROANILIDE	0.0268	1
ALA-ALA-PHE-7-AMIDO-4-CARBAMOYLMETHYLCOUMARIN	0.233	1
ALA-ALA-PHE-P-NITROPHENYLALANYL-ARG-LEU	0.0148	1
ALA-ALA-PRO-4-NITROANILIDE	0.888	1
ALA-ASP-PHE-P-NITROPHENYLALANYL-ARG-LEU	0.0051	1
ALA-HIS-PHE-P-NITROPHENYLALANYL-ARG-LEU	0.0422	1
ALA-NLE-LEU-7-AMIDO-4-CARBAMOYLMETHYLCOUMARIN	0.028	1
ALA-NLE-NLE-7-AMIDO-4-CARBAMOYLMETHYLCOUMARIN	0.037	1
ALA-NVA-NLE-7-AMIDO-4-CARBAMOYLMETHYLCOUMARIN	0.03	1
ALA-PHE-PRO-P-NITROANILIDE	0.437	1
ALA-SER-PHE-P-NITROPHENYLALANYL-ARG-LEU	0.0483	1
ARG-ALA-PHE-P-NITROPHENYLALANYL-ARG-LEU	0.0193	1
ARG-PRO-PHE-7-AMIDO-4-CARBAMOYLMETHYLCOUMARIN	0.054	1

UniProt features (118 total): sequence variant 41, strand 24, helix 17, turn 9, binding site 5, glycosylation site 5, mutagenesis site 4, disulfide bond 3, active site 3, sequence conflict 2, signal peptide 1, propeptide 1, chain 1, splice variant 1, domain 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3EDY	X-RAY DIFFRACTION	1.85
3EE6	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14773-F1	90.70	0.80

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): 272 (charge relay system); 276 (charge relay system); 475 (charge relay system)

Ligand- & substrate-binding residues (5): 541; 543; 517; 518; 539

Disulfide bonds (3): 111–122, 365–526, 522–537

Glycosylation sites (5): 210, 222, 286, 313, 443

Mutagenesis-validated functional residues (4):

Position	Phenotype
236	no effect.
360	inactive. impaired processing.
475	inactive. impaired processing.
517	inactive. impaired processing.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-381038	XBP1(S) activates chaperone genes

MSigDB gene sets: 360 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, KOBAYASHI_EGFR_SIGNALING_24HR_UP, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, WWTAAGGC_UNKNOWN, GOBP_VACUOLE_ORGANIZATION, BASSO_B_LYMPHOCYTE_NETWORK, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KEGG_LYSOSOME, WEIGEL_OXIDATIVE_STRESS_BY_TBH_AND_H2O2, WIELAND_UP_BY_HBV_INFECTION, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, GOBP_PEPTIDE_METABOLIC_PROCESS

GO Biological Process (12): proteolysis (GO:0006508), lipid metabolic process (GO:0006629), lysosome organization (GO:0007040), nervous system development (GO:0007399), central nervous system development (GO:0007417), protein catabolic process (GO:0030163), epithelial cell differentiation (GO:0030855), peptide catabolic process (GO:0043171), bone resorption (GO:0045453), neuromuscular process controlling balance (GO:0050885), protein localization to chromosome, telomeric region (GO:0070198), lysosomal protein catabolic process (GO:1905146)

GO Molecular Function (11): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), tripeptidyl-peptidase activity (GO:0008240), lysophosphatidic acid binding (GO:0035727), peptide binding (GO:0042277), metal ion binding (GO:0046872), sulfatide binding (GO:0120146), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (7): lysosome (GO:0005764), Golgi apparatus (GO:0005794), melanosome (GO:0042470), lysosomal lumen (GO:0043202), membrane raft (GO:0045121), recycling endosome (GO:0055037), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
IRE1alpha activates chaperones	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
system development	2
lysosome	2
peptidase activity	2
binding	2
primary metabolic process	1
lytic vacuole organization	1
nervous system development	1
macromolecule catabolic process	1
cell differentiation	1
epithelium development	1
peptide metabolic process	1
catabolic process	1
tissue homeostasis	1
bone remodeling	1
musculoskeletal movement	1
neuromuscular process	1
protein localization to chromosome	1
protein catabolic process in the vacuole	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
serine-type exopeptidase activity	1
phospholipid binding	1
anion binding	1
carbohydrate derivative binding	1
cation binding	1
glycolipid binding	1
catalytic activity	1
lytic vacuole	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
pigment granule	1
vacuolar lumen	1
membrane microdomain	1
endosome	1
extracellular vesicle	1

Protein interactions and networks

STRING

1492 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TPP1	TINF2	Q9BSI4	994
TPP1	TERF1	P54274	993
TPP1	POT1	Q9NUX5	992
TPP1	PPT1	P50897	957
TPP1	FLI1	Q01543	936
TPP1	CLN3	Q13286	909
TPP1	NUPR2	A6NF83	820
TPP1	DNAJC5	Q9H3Z4	778
TPP1	CLN6	Q9NWW5	773
TPP1	CLN5	O75503	767
TPP1	TERF2IP	Q9NYB0	744
TPP1	CLN8	Q9UBY8	737
TPP1	TERF2	Q15554	735
TPP1	CTSD	P07339	714
TPP1	ANAPC11	Q9NYG5	689

IntAct

109 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
CISH	TPP1	psi-mi:“MI:0915”(physical association)	0.560
TPP1	USP5	psi-mi:“MI:0915”(physical association)	0.560
TRAF4	TPP1	psi-mi:“MI:0915”(physical association)	0.560
WWP2	TPP1	psi-mi:“MI:0915”(physical association)	0.560
TPP1	FBXL4	psi-mi:“MI:0915”(physical association)	0.560
FBXO42	TPP1	psi-mi:“MI:0915”(physical association)	0.560
CEP55	TPP1	psi-mi:“MI:0915”(physical association)	0.560
OTUB1	TPP1	psi-mi:“MI:0915”(physical association)	0.560
RNF183	TPP1	psi-mi:“MI:0915”(physical association)	0.560
ASB6	TPP1	psi-mi:“MI:0915”(physical association)	0.560
ZBTB38	TPP1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (138): USP7 (Affinity Capture-Western), TPP1 (Affinity Capture-Western), TINF2 (Affinity Capture-Western), TERT (Affinity Capture-Western), POT1 (Affinity Capture-Western), CTC1 (Affinity Capture-Western), OBFC1 (Affinity Capture-Western), TINF2 (Reconstituted Complex), TERT (Reconstituted Complex), POT1 (Reconstituted Complex), CTC1 (Reconstituted Complex), OBFC1 (Reconstituted Complex), TPP1 (Affinity Capture-MS), TPP1 (Affinity Capture-MS), TPP1 (Affinity Capture-MS)

ESM2 similar proteins: A0JND9, E1BPW0, O14773, O18956, O35795, O55026, O75173, O75355, O75356, O75578, O89023, O93295, P08514, P08648, P11688, P17405, P49961, P55772, P56201, P79784, P97687, Q04519, Q0VD19, Q12794, Q32M88, Q49HH9, Q49KI5, Q5DRK1, Q5IS74, Q5MY95, Q5RFL1, Q5RFQ8, Q60HH1, Q6P3E7, Q6P6S9, Q717C1, Q717C2, Q7RTX0, Q8BFW6, Q8BNJ2

Diamond homologs: C5FBW2, C5FRX4, C5FTQ5, D4AIK6, D4AK75, D4ANG0, D4D7N6, D4D9U2, D4DBH6, F8W2M8, O14773, O89023, Q0V8B6, Q4WQU0, Q5IS74, Q5RFL1, Q60HH1, Q70GH4, Q70J59, Q9EQV6, Q9XSB8, C5FHK0, Q8GB88, Q8RR56, Q8NK92, Q70DX9, Q55CT0, Q8MZS4

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
TPP1	up-regulates	Telomere_maintenance
RNF8	“up-regulates activity”	TPP1	ubiquitination
TFEB	“up-regulates quantity by expression”	TPP1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1278 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	98
Likely pathogenic	83
Uncertain significance	441
Likely benign	484
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065450	NM_000391.4(TPP1):c.987_989del (p.Glu329del)	Pathogenic
1068518	NM_000391.4(TPP1):c.38_68del (p.Leu13fs)	Pathogenic
1073169	NM_000391.4(TPP1):c.1218T>A (p.Tyr406Ter)	Pathogenic
1073897	NM_000391.4(TPP1):c.1626G>A (p.Trp542Ter)	Pathogenic
1074191	NM_000391.4(TPP1):c.1323_1326del (p.Ser440_Tyr441insTer)	Pathogenic
1074509	NM_000391.4(TPP1):c.754_757del (p.Ala252fs)	Pathogenic
1074909	NM_000391.4(TPP1):c.408del (p.Glu137fs)	Pathogenic
1076930	NM_000391.4(TPP1):c.509-2A>G	Pathogenic
1373459	NM_000391.4(TPP1):c.1468G>T (p.Glu490Ter)	Pathogenic
1386990	NM_000391.4(TPP1):c.1540G>T (p.Gly514Ter)	Pathogenic
1409463	NM_000391.4(TPP1):c.52A>T (p.Lys18Ter)	Pathogenic
1416477	NC_000011.10:g.6615330del	Pathogenic
1416739	NM_000391.4(TPP1):c.177_194del (p.Arg60_Val65del)	Pathogenic
1452558	NM_000391.4(TPP1):c.1496del (p.Pro499fs)	Pathogenic
1455654	NM_000391.4(TPP1):c.1548_1551dup (p.Val518Ter)	Pathogenic
1458603	NM_000391.4(TPP1):c.472C>T (p.Gln158Ter)	Pathogenic
1459474	NM_000391.4(TPP1):c.1558del (p.Arg520fs)	Pathogenic
1471492	NM_000391.4(TPP1):c.3G>C (p.Met1Ile)	Pathogenic
1675447	NM_000391.4(TPP1):c.1288_1289dup (p.Leu430_Ser431insTer)	Pathogenic
1686271	NM_000391.4(TPP1):c.899del (p.Gly300fs)	Pathogenic
1696130	NM_000391.4(TPP1):c.790C>T (p.Gln264Ter)	Pathogenic
188850	NM_000391.4(TPP1):c.972_979del (p.Ser324fs)	Pathogenic
189179	NM_000391.4(TPP1):c.1379G>A (p.Trp460Ter)	Pathogenic
1995567	NM_000391.4(TPP1):c.1477_1478dup (p.Leu494fs)	Pathogenic
1995893	NM_000391.4(TPP1):c.702T>G (p.Tyr234Ter)	Pathogenic
2001644	NM_000391.4(TPP1):c.966del (p.Thr322_Val323insTer)	Pathogenic
2012420	NM_000391.4(TPP1):c.917del (p.Gln306fs)	Pathogenic
2028961	NM_000391.4(TPP1):c.175_195del (p.Glu59_Val65del)	Pathogenic
207561	NM_000391.4(TPP1):c.311T>A (p.Leu104Ter)	Pathogenic
207564	NM_000391.4(TPP1):c.196C>T (p.Gln66Ter)	Pathogenic

SpliceAI

1902 predictions. Top by Δscore:

Variant	Effect	Δscore
11:6615165:TCTCA:T	donor_loss	1.0000
11:6615166:CTCA:C	donor_loss	1.0000
11:6615167:TCA:T	donor_loss	1.0000
11:6615168:CA:C	donor_loss	1.0000
11:6615169:A:AC	donor_gain	1.0000
11:6615169:A:C	donor_loss	1.0000
11:6615170:C:CA	donor_loss	1.0000
11:6615170:C:CC	donor_gain	1.0000
11:6615328:TC:T	acceptor_gain	1.0000
11:6615328:TCC:T	acceptor_loss	1.0000
11:6615329:CC:C	acceptor_gain	1.0000
11:6615330:C:A	acceptor_loss	1.0000
11:6615330:C:CC	acceptor_gain	1.0000
11:6615331:T:C	acceptor_loss	1.0000
11:6615439:TACC:T	donor_loss	1.0000
11:6615441:CCT:C	donor_loss	1.0000
11:6615558:AGGGG:A	acceptor_gain	1.0000
11:6615559:GGGG:G	acceptor_gain	1.0000
11:6615560:GGG:G	acceptor_gain	1.0000
11:6615561:GG:G	acceptor_gain	1.0000
11:6615563:C:CC	acceptor_gain	1.0000
11:6616003:A:AC	donor_gain	1.0000
11:6616004:C:CC	donor_gain	1.0000
11:6616075:C:CG	acceptor_loss	1.0000
11:6617149:CCCCA:C	acceptor_gain	1.0000
11:6617150:CCCA:C	acceptor_gain	1.0000
11:6617150:CCCAC:C	acceptor_gain	1.0000
11:6617151:CCA:C	acceptor_gain	1.0000
11:6617151:CCAC:C	acceptor_gain	1.0000
11:6617152:CA:C	acceptor_gain	1.0000

AlphaMissense

3630 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:6614987:G:A	S477F	0.998
11:6616418:G:C	S324R	0.998
11:6616418:G:T	S324R	0.998
11:6616420:T:G	S324R	0.998
11:6614612:C:A	W542C	0.997
11:6614612:C:G	W542C	0.997
11:6614987:G:T	S477Y	0.997
11:6615562:G:C	S382R	0.997
11:6615562:G:T	S382R	0.997
11:6616006:T:G	S382R	0.997
11:6616071:T:A	D360V	0.997
11:6616818:G:C	F243L	0.997
11:6616818:G:T	F243L	0.997
11:6616820:A:G	F243L	0.997
11:6614614:A:G	W542R	0.996
11:6614614:A:T	W542R	0.996
11:6615472:G:C	F412L	0.996
11:6615472:G:T	F412L	0.996
11:6615474:A:G	F412L	0.996
11:6615484:A:C	S408R	0.996
11:6615484:A:T	S408R	0.996
11:6615486:T:G	S408R	0.996
11:6616016:G:C	F378L	0.996
11:6616016:G:T	F378L	0.996
11:6616018:A:G	F378L	0.996
11:6614598:C:T	G547D	0.995
11:6614970:C:A	G483W	0.995
11:6614973:C:A	G482W	0.995
11:6615469:G:C	S413R	0.995
11:6615469:G:T	S413R	0.995

dbSNP variants (sampled 300 via entrez): RS1000206261 (11:6619523 A>G,T), RS1000290348 (11:6616805 C>T), RS1000448284 (11:6612990 C>G,T), RS1000719227 (11:6613562 A>T), RS1000760995 (11:6619304 G>A,T), RS1002024038 (11:6619962 G>A,C), RS1002916214 (11:6615872 A>G), RS1003329507 (11:6621121 A>G), RS1003951253 (11:6618432 G>A,C), RS1004333669 (11:6612873 T>G), RS1004451081 (11:6613142 T>C), RS1005007686 (11:6619536 G>A,T), RS1005091366 (11:6613369 A>G), RS1005161922 (11:6620018 T>C), RS1005235580 (11:6620237 T>A,C)

Disease associations

OMIM: gene MIM:607998 | disease phenotypes: MIM:204500, MIM:609270, MIM:256730, MIM:105830

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronal ceroid lipofuscinosis	Definitive	Autosomal recessive
neuronal ceroid lipofuscinosis 2	Definitive	Autosomal recessive
autosomal recessive spinocerebellar ataxia 7	Strong	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 2 (MONDO:0008769), autosomal recessive spinocerebellar ataxia 7 (MONDO:0012235), neuronal ceroid lipofuscinosis (MONDO:0016295), Angelman syndrome (MONDO:0007113), intellectual disability (MONDO:0001071), congenital nervous system disorder (MONDO:0002320), retinal disorder (MONDO:0005283), juvenile neuronal ceroid lipofuscinosis (MONDO:0019262)

Orphanet (8): OBSOLETE: Late infantile neuronal ceroid lipofuscinosis (Orphanet:168491), CLN2 disease (Orphanet:228349), OBSOLETE: Juvenile neuronal ceroid lipofuscinosis (Orphanet:79264), Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia (Orphanet:284324), Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), Angelman syndrome (Orphanet:72), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D017204	Angelman Syndrome	C10.228.662.075; C16.131.077.095; C16.131.260.040; C16.320.180.040; C16.320.447.250
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D012164	Retinal Diseases	C11.768
C531619	Happy puppet syndrome (formerly) (supp.)
C563753	Spinocerebellar Ataxia, Autosomal Recessive 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067052 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.47	Kd	3389	nM	CHEMBL3752910
5.47	ED50	3389	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 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-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149645: Binding affinity to human TPP1 incubated for 45 mins by Kinobead based pull down assay	kd	3.3893	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	7
bisphenol A	decreases methylation, decreases expression, increases expression, affects expression, affects cotreatment	5
bisphenol F	increases expression, affects cotreatment, decreases methylation	3
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases palmitoylation, decreases expression	3
sodium arsenite	affects expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	2
bisphenol S	increases expression, affects cotreatment	2
Air Pollutants	affects expression, increases abundance, increases expression	2
Cadmium	increases abundance, increases palmitoylation, decreases expression, decreases reaction	2
Lead	decreases expression, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
tert-Butylhydroperoxide	decreases expression	2
aristolochic acid I	decreases expression	1
abemaciclib	increases expression	1
afuresertib	increases expression	1
dicrotophos	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
sodium arsenate	increases abundance, increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
gossypol acetic acid	increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
yessotoxin	increases expression	1
perfluorooctane sulfonic acid	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652687	Binding	Binding affinity to human TPP1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

40 cell lines: 11 transformed cell line, 10 induced pluripotent stem cell, 7 embryonic stem cell, 7 cancer cell line, 5 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_A7HB	WAe009-A-49	Embryonic stem cell	Female
CVCL_A7HC	WAe009-A-51	Embryonic stem cell	Female
CVCL_A7HD	WAe009-A-52	Embryonic stem cell	Female
CVCL_A7HE	WAe009-A-53	Embryonic stem cell	Female
CVCL_A7HF	WAe009-A-54	Embryonic stem cell	Female
CVCL_A7HG	WAe009-A-55	Embryonic stem cell	Female
CVCL_B3W0	WG0305	Finite cell line
CVCL_B3W1	WG0308	Finite cell line
CVCL_B3W2	C7786	Transformed cell line
CVCL_B3W3	C7787	Transformed cell line

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT01955135	PHASE4	COMPLETED	Anesthesia for Retinopathy of Prematurity
NCT02893254	PHASE3	COMPLETED	Efficacy and Safety of IBI303 in Adult Patients With Active Ankylosing Spondylitis
NCT03882918	PHASE3	TERMINATED	An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome
NCT06415344	PHASE3	ENROLLING_BY_INVITATION	Long-term Extension of GTX-102 in Angelman Syndrome
NCT06617429	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Efficacy and Safety Study of GTX-102 in Pediatric Subjects With Angelman Syndrome (AS)
NCT06914609	PHASE3	RECRUITING	REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome
NCT07605429	PHASE3	NOT_YET_RECRUITING	Phase III Clinical Study of Rugonersen in Angelman 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
NCT02056665	PHASE2	COMPLETED	Study to Evaluate the Efficacy and Safety of Minocycline in Angelman Syndrome
NCT02996305	PHASE2	COMPLETED	A Study in Adults and Adolescents With Angelman Syndrome (STARS)
NCT05011851	PHASE2	COMPLETED	An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome
NCT05630066	PHASE2	COMPLETED	A Study to Investigate the Pharmacokinetics (PK) and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents Aged 5-17 Years With Angelman Syndrome (AS) With Deletion Genotype.
NCT07157254	PHASE2	RECRUITING	A Safety and Efficacy Study of GTX-102 in Subjects With Deletion- or Nondeletion-type Angelman Syndrome (AS)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01373476	PHASE2	COMPLETED	Multicentre, Randomized, Controlled Trial of Qideng Mingmu Capsule in The Treatment of Diabetic Retinopathy
NCT01793090	PHASE2	COMPLETED	EPI-743 in Cobalamin C Defect: Effects on Visual and Neurological Impairment
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT00151216	PHASE1	COMPLETED	Safety Study of a Gene Transfer Vector for Children With Late Infantile Neuronal Ceroid Lipofuscinosis
NCT00829439	PHASE1	COMPLETED	Study on Tolerability of Levodopa/Carbidopa in Children With Angelman Syndrome
NCT03109756	PHASE1	COMPLETED	Single Dose Pharmacokinetic (PK) Study
NCT04428281	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of RO7248824 in Participants With Angelman Syndrome (AS)
NCT04863794	PHASE1	COMPLETED	A Study To Assess Distribution Of RO7248824 In The Central Nervous System Following Single Intrathecal Doses Of [89zr] Labeled RO7248824 In Healthy Male Participants
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT01966757	Not specified	COMPLETED	Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT06844877	Not specified	RECRUITING	Italian NCL Registry: a Registry for NCL as an Integration Tool for Future Therapeutic Strategies