TPP1
protein-codingtripeptidyl peptidase 1
Gene summary
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. [provided by RefSeq, Jul 2008]
- CLN2
- SCAR7
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~6.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0012235
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0012235
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: Myriad Women's Health
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0016295
Submitter: ClinGen
Neuronal ceroid lipofuscinoses (NCLs) are progressive neurodegenerative diseases characterized by mental and motor deterioration, epilepsy, visual loss, ataxia, and a reduced life span. The unifying finding in NCL patients is the accumulation, in neurons and many other cell types, of autofluorescent storage material. There are 13 subtypes of NCLs that are categorized based on the particular gene that is mutated. TPP1 is associated with autosomal recessive NCL2, with typical onset at age 2-4, and is described as late infantile NCL (LINCL). Besides NCL, TPP1 has been associated with autosomal recessive spinocerebellar ataxia, characterized by progressive motor deficits and cerebellar atrophy. This gene-disease association was not curated, because it was only reported once in two Dutch families with the same compound heterozygous variants (c.509-1G>C/ p.Val466Gly; PMID: 23428007). Two other cases that were described as TPP1-associated spinocerebellar ataxia had questionable gene-disease association, because they had intellectual impairment (PMID: 26224725, 27217339). NCL2 was first reported to be associated with TPP1 in 1997 in a study that identified its product as a lysosomal protein absent in a patient with LINCL (Sleat et al. 1997 PMID: 9295267). Since then, 131 independent variants have been reported according to Gardner et al. 2019 (PMID: 31283065). Of the 131 variants, there were 63 missense, 21 frameshift, 17 nonsense, 22 splicing, and 8 other types of variants (https://www.ucl.ac.uk/ncl//mutation.shtml). While many of the variants were unique to each family, two variants, c.509-1G>C and c.622C>T (p.Arg208*) in NM_000391.3, collectively occurred in 60% of individuals reported and accounted for 50% of disease‐associated alleles (31283065). Fifteen symptomatic probands from 15 families with homozygous or compound heterozygous TPP1 variants reported by six studies were scored for genetic evidence (PMID: 10330339, 12376936, 17959406, 19793312, 27343025, 30541466). Six probands had two variants in trans that were not predicted/proven to be null, and were given scores ranging from 0 to 1. The remaining nine probands had at least one of the two variants in trans that were proven/predicted to be null, and were given scores ranging from 0 to 2. For ten probands, reduced TPP1 activity in patient cells was used to upgrade the points, whereas functional studies were used to upgrade the points for two probands in one study (12376936), because the results of TPP1 enzyme activity in patient cells were not available. No LOD scores could be calculated from these families, because only single affected individual was reported for each case. Supporting experimental evidence includes protein interaction with CLN5 (12134079), non-human model organisms (mouse: 15483130; dog: 16621647), and rescue in non-human model organisms by adeno associated virus-mediated gene transfer (mouse: 17637720; dog: 26560358). Additional non-human model organism studies in dog (18344450, 21745338) and gene transfer studies mouse (16452657, 17180118, 18639872) were also reviewed as supporting evidence. Furthermore, enzyme replacement therapies on mouse (18362923, 21730969, 24394185, 24394185, 28345005), dog (21784683, 24938720, 24954537, 25257657), and human (29688815) were reviewed, although not scored. In summary, a score of 12 was given to genetic evidence, and 3.5 to experimental evidence, reaching 15.5 in total. TPP1’s association with NCL is upgraded from strong to definitive, because it has been replicated for more than two decades.
Inheritance Pattern: AR
Disease ID:MONDO:0008769
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic; Ophthalmologic
Intervention: Neurologic
Rationale: The condition involves neurodevelopmental sequelae, and intraventricular administration of cerliponase alfa has been reported as showing neurological benefit
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to TPP1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000391.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 6 | 310 | 1 | 318 | |
| missense | 12 | 57 | 394 | 31 | 494 | |
| nonsense | 32 | 13 | 2 | 47 | ||
| start loss | 1 | 1 | ||||
| frameshift | 40 | 43 | 83 | |||
| splice donor/acceptor (+/-2bp) | 13 | 28 | 5 | 46 | ||
| Total | 98 | 142 | 407 | 341 | 1 | 989 |
Highest pathogenic variant AF is 0.0012602387
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000382.3 | 13 | MANE Select | |
| Ensembl | ENSP00000299427.6 | 13 | MANE Select | |
| Ensembl | ENSP00000398136.3 | 6 | Standard | |
| Ensembl | ENSP00000434647.1 | 3 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| tpp1 | Danio rerio | Structure: mandibular arch skeleton Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Lysosome - Homo sapiens (human)
- XBP1(S) activates chaperone genes
Biological Process
- proteolysis
- lipid metabolic process
- lysosome organization
- nervous system development
- central nervous system development
Molecular Function
- endopeptidase activity
- serine-type endopeptidase activity
- protein binding
- peptidase activity
- serine-type peptidase activity
Cellular Component
- lysosome
- melanosome
- lysosomal lumen
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000299427
- Coding exons
- 13
- Length
- 6693
- Individuals with no LoFs
- 125536
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 212
- Defined
- 125748
- p
- 0.000843
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.221 | 321 | 310 | 1.04 | 0.0000179 | 3614 |
| Missense (PolyPhen) | 107 | 120.1 | 0.89093 | 1425 | ||
| Synonymous | -0.160 | 127 | 125 | 1.02 | 0.00000674 | 1190 |
| Loss of Function | 2.48 | 15 | 29.5 | 0.508 | 0.00000148 | 309 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00064 | 0.00064 | rare |
| Ashkenazi Jewish | 0.00050 | 0.00050 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.00032 | 0.00032 | rare |
| European (Non-Finnish) | 0.0015 | 0.0015 | notable |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00081 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- 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 (By similarity). {ECO:0000250|UniProtKB:Q9EQV6}.;
- Disease
- DISEASE: 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. {ECO:0000269|PubMed:10330339, ECO:0000269|PubMed:10665500, ECO:0000269|PubMed:11241479, ECO:0000269|PubMed:11339651, ECO:0000269|PubMed:11589012, ECO:0000269|PubMed:12376936, ECO:0000269|PubMed:12414822, ECO:0000269|PubMed:12698559, ECO:0000269|PubMed:14736728, ECO:0000269|PubMed:19201763, ECO:0000269|PubMed:20340139, ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:22612257, ECO:0000269|PubMed:9295267}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spinocerebellar ataxia, autosomal recessive, 7 (SCAR7) [MIM:609270]: Spinocerebellar ataxia defines 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. {ECO:0000269|PubMed:23418007}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.280
Intolerance Scores
- LoFtool
- 0.115
- RVIS EVS
- 0.4
- RVIS percentile EVS
- 76.41
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.771
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |