GeneBe

HTRA1

protein-coding

HtrA serine peptidase 1, the group of Serine proteases|PDZ domain containing

Gene summary

This gene encodes a member of the trypsin family of serine proteases. This protein is a secreted enzyme that is proposed to regulate the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. It has also been suggested to be a regulator of cell growth. Variations in the promoter region of this gene are the cause of susceptibility to age-related macular degeneration type 7. [provided by RefSeq, Jul 2008]

Previous symbols:
  • PRSS11

MANE transcript

NM_002775.5

Inheritance

AD, AR

ClinVar variants

P:54U:187B:95

Top phenotype

Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2); Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr10:122,458,551-122,514,907

External References & Databases

Ensembl (ENSG00000166033)NCBI Gene (5654)OMIM (602194)HGNC:9476GenCCUniProt (Q92743)AlphaFoldClinVar (HTRA1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~56.4 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014768

Submitter: PanelApp Australia

cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010829

Submitter: PanelApp Australia

cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010829

Submitter: Labcorp Genetics (formerly Invitae)

cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010829

Submitter: Orphanet

genetic cerebral small vessel diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018787

Submitter: Franklin by Genoox

HTRA1-related autosomal dominant cerebral small vessel diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018832

Submitter: Orphanet

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014768

Submitter: Genomics England PanelApp

cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010829

Submitter: Genomics England PanelApp

HTRA1-related autosomal dominant cerebral small vessel diseaseMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018832

Submitter: Ambry Genetics

cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010829

Submitter: Ambry Genetics

cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014768

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2); Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)AD/AR

Manifestation: Cardiovascular; Dermatologic; 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

Refs: 17053108; 17053109; 17884985; 17568988; 18511946; 19387015; 20437615; 21115960; 21482952; 22900900; 24500651; 26063658Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HTRA1 variants in ClinVar

20 Conditions Cataloged
not providedTotal: 277
not specifiedTotal: 63
Inborn genetic diseasesTotal: 41
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2Total: 40
HTRA1-related disorderTotal: 35
Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 2Total: 28
Macular degenerationTotal: 24
HTRA1-related disordersTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002775.5. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
84
clinvar
1
clinvar
 89
missense
7
clinvar
22
clinvar
172
clinvar
7
clinvar
1
clinvar
 209
nonsense
2
clinvar
9
clinvar
2
clinvar
 13
start loss
0
frameshift
3
clinvar
5
clinvar
3
clinvar
2
clinvar
 13
splice donor/acceptor (+/-2bp)
1
clinvar
5
clinvar
6
clinvar
 12
Total1341187932336

Highest pathogenic variant AF is 0.000044626864

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002775.5RefSeqNP_002766.19MANE Select
ENST00000368984.8EnsemblENSP00000357980.39MANE Select
ENST00000420892.1EnsemblENSP00000412676.16Standard
ENST00000648167.1EnsemblENSP00000498033.19Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
htra1aDanio rerio

Structure: caudal fin lower lobe

Quality: absent

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Extracellular matrix organization
  • Degradation of the extracellular matrix

Biological Process

  • regulation of cell growth
  • placenta development
  • proteolysis
  • extracellular matrix disassembly
  • negative regulation of transforming growth factor beta receptor signaling pathway

Molecular Function

  • serine-type endopeptidase activity
  • protein binding
  • insulin-like growth factor binding
  • serine-type peptidase activity
  • identical protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • cytosol
  • plasma membrane
  • collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000368984
Coding exons
9
Length
53384
Individuals with no LoFs
125732
Homozygous LoFs
0
Heterozygous LoFs
16
Defined
125748
p
0.0000636
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.051952410.8090.00001643042
Missense (PolyPhen)78114.970.678431293
Synonymous-0.5101091021.060.000007981010
Loss of Function2.41920.90.4310.00000146225

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000160.00016rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.0000530.000053rare
South Asian0.0000650.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets. {ECO:0000269|PubMed:16377621, ECO:0000269|PubMed:20671064, ECO:0000269|PubMed:9852107}.;
Disease
DISEASE: Macular degeneration, age-related, 7 (ARMD7) [MIM:610149]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:17053108, ECO:0000269|PubMed:17053109}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy (CARASIL) [MIM:600142]: A cerebrovascular disease characterized by non- hypertensive arteriopathy of cerebral small vessels with subcortical infarcts, alopecia, and spondylosis. Small cerebral arteries show arteriosclerotic changes, fibrous intimal proliferation, and hyaline degeneration with splitting of the intima and/or the internal elastic membrane. Neurologic features include progressive dementia, gait disturbances, extrapyramidal and pyramidal signs, and demyelination of the cerebral white matter with sparing of U fibers. {ECO:0000269|PubMed:19387015}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 2 (CADASIL2) [MIM:616779]: A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. {ECO:0000269|PubMed:26063658}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.332

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.326

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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