HTRA1 (HtrA serine peptidase 1)

Gene

• Entrez ID: 5654
• Gene name: HtrA serine peptidase 1
• Gene symbol: HTRA1
• Synonyms: ARMD7, CADASIL2, CARASIL, HtrA, L56, ORF480, PRSS11
• Chromosome: 10
• Chromosome location: 10q26.13
• 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]

SNPs

SNP ID	Visualize variation	Clinical significance	Consequence
rs113993969	G>A	Pathogenic	Missense variant, coding sequence variant
rs113993970	C>T	Pathogenic, likely-pathogenic	Stop gained, coding sequence variant
rs113993971	C>T	Pathogenic, likely-pathogenic	Stop gained, coding sequence variant
rs149294320	C>A,T	Uncertain-significance, conflicting-interpretations-of-pathogenicity, likely-benign	Coding sequence variant, synonymous variant
rs373287445	C>A,G,T	Conflicting-interpretations-of-pathogenicity	Coding sequence variant, synonymous variant
rs587776445	G>A	Pathogenic	Coding sequence variant, missense variant
rs587776447	T>C	Pathogenic	Coding sequence variant, missense variant
rs587776449	G>A	Pathogenic	Coding sequence variant, missense variant
rs587776873	G>A,C	Pathogenic	Coding sequence variant, missense variant
rs864622782	C>A	Pathogenic	Coding sequence variant, missense variant
rs864622783	G>A	Pathogenic	Splice acceptor variant
rs1267457680	A>C,G	Likely-pathogenic	Missense variant, coding sequence variant
rs1554952277	G>C	Likely-pathogenic	Missense variant, coding sequence variant
rs1554952291	C>T	Pathogenic	Stop gained, coding sequence variant

miRNA

miRTarBase ID	miRNA	Experiments	Reference
MIRT021015	hsa-miR-155-5p	Proteomics	18668040
MIRT030211	hsa-miR-26b-5p	Microarray	19088304
MIRT032028	hsa-miR-16-5p	Proteomics	18668040
MIRT646005	hsa-miR-6774-5p	HITS-CLIP	23824327
MIRT646006	hsa-miR-635	HITS-CLIP	23824327
MIRT646007	hsa-miR-186-3p	HITS-CLIP	23824327

Gene ontology (GO)

GO ID	Ontology	Definition	Evidence	Reference
GO:0001890	Process	Placenta development	IEA
GO:0004252	Function	Serine-type endopeptidase activity	IEA
GO:0005515	Function	Protein binding	IPI	25002585, 26436840, 28726057, 29572155
GO:0005520	Function	Insulin-like growth factor binding	IEA
GO:0005576	Component	Extracellular region	TAS
GO:0005615	Component	Extracellular space	TAS	9852107
GO:0005829	Component	Cytosol	IEA
GO:0005886	Component	Plasma membrane	IDA
GO:0006508	Process	Proteolysis	ISS
GO:0008236	Function	Serine-type peptidase activity	ISS
GO:0022617	Process	Extracellular matrix disassembly	TAS
GO:0030512	Process	Negative regulation of transforming growth factor beta receptor signaling pathway	IEA
GO:0030514	Process	Negative regulation of BMP signaling pathway	IEA
GO:0042802	Function	Identical protein binding	IPI	21297635, 22578544, 28642151
GO:0050679	Process	Positive regulation of epithelial cell proliferation	IEA
GO:0050687	Process	Negative regulation of defense response to virus	IEA
GO:0060718	Process	Chorionic trophoblast cell differentiation	IEA
GO:0062023	Component	Collagen-containing extracellular matrix	HDA	23979707, 27068509
GO:0062023	Component	Collagen-containing extracellular matrix	HDA	20551380, 28327460
GO:0070062	Component	Extracellular exosome	HDA	19199708
GO:0097187	Process	Dentinogenesis	IEA

Other IDs

• MIM: 602194
• HGNC: 9476
• e!Ensembl: ENSG00000166033

Protein

• UniProt ID: Q92743
• Protein name: Serine protease HTRA1 (EC 3.4.21.-) (High-temperature requirement A serine peptidase 1) (L56) (Serine protease 11)
• Protein 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.
• PDB: 2JOA, 2YTW, 3NUM, 3NWU, 3NZI, 3TJN, 3TJO, 3TJQ
• Family and domains:

  Pfam

  Accession	ID	Position in sequence	Description	Type
  PF00219	IGFBP	37 → 89	Insulin-like growth factor binding protein	Domain
  PF07648	Kazal_2	108 → 155	Kazal-type serine protease inhibitor domain	Domain
  PF13365	Trypsin_2	204 → 342		Domain
  PF17820	PDZ_6	413 → 464	PDZ domain	Domain

• Sequence:

  MQIPRAALLPLLLLLLAAPASAQLSRAGRSAPLAAGCPDRCEPARCPPQPEHCEGGRARD
  ACGCCEVCGAPEGAACGLQEGPCGEGLQCVVPFGVPASATVRRRAQAGLCVCASSEPVCG
  SDANTYANLCQLRAASRRSERLHRPPVIVLQRGACGQGQEDPNSLRHKYNFIADVVEKIA
  PAVVHIELFRKLPFSKREVPVASGSGFIVSEDGLIVTNAHVVTNKHRVKVELKNGATYEA
  KIKDVDEKADIALIKIDHQGKLPVLLLGRSSELRPGEFVVAIGSPFSLQNTVTTGIVSTT
  QRGGKELGLRNSDMDYIQTDAIINYGNSGGPLVNLDGEVIGINTLKVTAGISFAIPSDKI
  KKFLTESHDRQAKGKAITKKKYIGIRMMSLTSSKAKELKDRHRDFPDVISGAYIIEVIPD
  TPAEAGGLKENDVIISINGQSVVSANDVSDVIKRESTLNMVVRRGNEDIMITVIPEEIDP
  

• Sequence length: 480

Pathways

Reactome:

Degradation of the extracellular matrix

Associated diseases

Causal
Disease name	Disease term	dbSNP ID	References
Age-related macular degeneration	Macular Degeneration, Age-Related, 7, Age related macular degeneration, NON RARE IN EUROPE: Age-related macular degeneration	rs2133900556, rs199474657, rs2274700, rs1410996, rs61750120, rs1800728, rs62654397, rs61749423, rs61751412, rs61749439, rs61751398, rs61752417, rs62645946, rs1801269, rs62646860, rs61750142, rs61750145, rs61750152, rs61751377, rs61753029, rs61751407, rs61751389, rs61750645, rs61750648, rs879255520, rs752147871, rs886044750, rs886044749, rs746541266, rs756840095, rs886044725, rs749526785, rs1057518955, rs1057518767, rs371489809, rs1064793014, rs1571264574, rs1659524475	17053108, 20385819, 23326517, 23577725, 28703135, 29346644
Coronary artery disease	Coronary Artery Disease	rs137852988, rs121918313, rs-1, rs121918529, rs121918531, rs137852340, rs405509, rs1555800701, rs1215189537	29212778
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy	CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2, Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy	rs113993970, rs864622781, rs781563777, rs864622782, rs864622783, rs1554948318, rs1554950655, rs1273355332, rs1554952277, rs1554952291, rs1267457680	24500651, 26063658, 24357685
Vascular leukoencephalopathy	Cerebral Autosomal Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy	rs28937321, rs28933696, rs28933697, rs864621964, rs864621965, rs28933698, rs137852641, rs137852642, rs864621966, rs267606915, rs797045014, rs863225297, rs1438626607, rs1285584068, rs1555727942, rs1188569102, rs1323608032, rs1555729451, rs1555729486, rs1174625611, rs775836288, rs1555729604, rs1555730176, rs1555730188, rs1555730189, rs201118034, rs1555729346, rs1568361608, rs200881673, rs1555730197, rs145069047, rs-1, rs1599382214, rs1202763005, rs764148985, rs769773673, rs762734007, rs1599391536, rs1599394806, rs760768552	22900900, 21482952, 25772074, 11889251, 24357685, 19387015, 21115960, 24535794, 24500651, 26063658, 25770224, 27164673, 25957642
Neurofibrosarcoma	Neurofibrosarcoma	rs137852604	27723760
Lung cancer	Malignant neoplasm of lung	rs121913530, rs121913529, rs878855122, rs1057519784, rs770315135	27935865
Moyamoya disease	Moyamoya Disease	rs121434527, rs121434528, rs387906592, rs397514563, rs797045187, rs1555675538, rs1568149971, rs1599150380, rs-1, rs2079443410
Leukoencephalopathy	Leukoencephalopathy	rs34757931

Unknown
Disease name	Disease term	dbSNP ID	References
Alopecia	Alopecia		26063658
Cadasil syndrome	CADASIL Syndrome
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy and migraine	CADASILM
Cerebral microangiopathy	Cerebral Small Vessel Diseases		26063658
Cerebral small vessel disease	HTRA1-related autosomal dominant cerebral small vessel disease
Dementia	Dementia		24500651
Dysarthria	Dysarthria
Exudative macular degeneration	Exudative age-related macular degeneration, exudative macular degeneration		28775256, 28703135
Impaired cognition	Impaired cognition		26063658
Intervertebral disc degeneration	Intervertebral Disc Degeneration		26063658
Lung neoplasms	Lung Neoplasms		27935865
Malignant peripheral nerve sheath tumor	Malignant Peripheral Nerve Sheath Tumor, Malignant peripheral nerve sheath tumor		27723760
Status cribrosum	Status cribrosum
Stroke	Cerebrovascular accident		29531354
Subcortical infarcts	Recurrent subcortical infarcts
Transient ischemic attack	Transient Ischemic Attack