HTRA2
protein-codingHtrA serine peptidase 2, the group of Serine proteases|PDZ domain containing
Gene summary
This gene encodes a serine protease. The protein has been localized in the endoplasmic reticulum and interacts with an alternatively spliced form of mitogen-activated protein kinase 14. The protein has also been localized to the mitochondria with release to the cytosol following apoptotic stimulus. The protein is thought to induce apoptosis by binding the apoptosis inhibitory protein baculoviral IAP repeat-containing 4. Nuclear localization of this protein has also been observed. Alternate splicing of this gene results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2016]
- PRSS25
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0044723
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0044723
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0044723
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0044723
Submitter: ClinGen
HTRA2 was first reported in relation to autosomal recessive 3-methylglutaconic aciduria type 8 in 2016 (Mandel H, et al., 2016, PMID: 27208207). HTRA2 encodes an ATP-independent serine protease that resides in the mitochondrial intermembrane space, but upon cellular stress, HTRA2 is processed to a shorter form and released into the cytosol. Here, it facilitates cell death through cleavage of apoptosis inhibitor proteins. Mutations in the gene lead to increased susceptibility to apoptosis and neurodegeneration. The clinical features include hypotonia, dystonia, seizures and cardio-respiratory difficulties. Urine analysis characteristically shows excretion of 3-methylglutaconic acid. Eight variants (missense, indel, frameshift, and splice variants) have been reported in 7 probands (and 3 family members) from 4 publications (PMIDs: 27208207, 27696117, 30114719, and 32445293). This gene-disease association is also supported by its biochemical functions in proteolytic cleavage and apoptosis (PMID: 11604410), which are altered in patient cells (PMIDs: 27696117. 27208207). As well two mouse models that recapitulate to the human phenotype (PMIDs: 15509788, 14534547). In summary, HTRA2 is definitively associated with autosomal recessive 3-methylglutaconic aciduria type 8.
Clinical Genomic Database (CGD)
Manifestation: Biochemical; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HTRA2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_013247.5. 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 | 2 | 96 | 98 | |||
| missense | 2 | 1 | 132 | 3 | 138 | |
| nonsense | 2 | 1 | 3 | 6 | ||
| start loss | 0 | |||||
| frameshift | 6 | 3 | 9 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 4 | 6 | ||
| Total | 11 | 6 | 141 | 99 | 0 | 257 |
Highest pathogenic variant AF is 0.00001634628
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_037379.1 | 8 | MANE Select | |
| Ensembl | ENSP00000258080.3 | 8 | MANE Select | |
| RefSeq | NP_001308656.1 | 7 | Standard | |
| RefSeq | NP_001308657.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Apoptosis - multiple species - Homo sapiens (human)
- Parkinson,s disease - Homo sapiens (human)
- Apoptosis - Homo sapiens (human)
- Apoptosis Modulation and Signaling
- Parkinsons Disease Pathway
Biological Process
- proteolysis
- ceramide metabolic process
- mitochondrion organization
- aging
- adult walking behavior
Molecular Function
- serine-type endopeptidase activity
- protein binding
- peptidase activity
- serine-type peptidase activity
- identical protein binding
Cellular Component
- chromatin
- nucleus
- mitochondrion
- mitochondrial intermembrane space
- endoplasmic reticulum
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000258080
- Coding exons
- 8
- Length
- 3969
- Individuals with no LoFs
- 125718
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 30
- Defined
- 125748
- p
- 0.000119
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.70 | 186 | 264 | 0.705 | 0.0000147 | 2838 |
| Missense (PolyPhen) | 71 | 132.31 | 0.53662 | 1495 | ||
| Synonymous | 0.0507 | 108 | 109 | 0.994 | 0.00000547 | 1094 |
| Loss of Function | 2.31 | 7 | 17.4 | 0.403 | 9.96e-7 | 186 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.00014 | 0.00014 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine protease that shows proteolytic activity against a non-specific substrate beta-casein. Promotes or induces cell death either by direct binding to and inhibition of BIRC proteins (also called inhibitor of apoptosis proteins, IAPs), leading to an increase in caspase activity, or by a BIRC inhibition-independent, caspase-independent and serine protease activity-dependent mechanism. Cleaves THAP5 and promotes its degradation during apoptosis. Isoform 2 seems to be proteolytically inactive. {ECO:0000269|PubMed:15200957, ECO:0000269|PubMed:19502560}.;
- Disease
- DISEASE: 3-methylglutaconic aciduria 8 (MGCA8) [MIM:617248]: An autosomal recessive inborn error of metabolism resulting in early death. Clinical features include extreme hypertonia observed at birth, alternating with hypotonia, subsequent appearance of extrapyramidal symptoms, lack of psychomotor development, microcephaly, and intractable seizures. Patients show lactic acidemia, 3-methylglutaconic aciduria, intermittent neutropenia, and progressive brain atrophy. {ECO:0000269|PubMed:27208207, ECO:0000269|PubMed:27696117}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parkinson disease 13 (PARK13) [MIM:610297]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability, as well as by a clinically significant response to treatment with levodopa. The pathology involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. {ECO:0000269|PubMed:15961413, ECO:0000269|PubMed:18401856}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.379
Intolerance Scores
- LoFtool
- 0.416
- RVIS EVS
- 0.28
- RVIS percentile EVS
- 71.27
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.801
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |