The gene encompasses 53384 bases of DNA. The coding part is composed of nine exons.

HTRA1 mRNA product, length of 2138 bases, has an open frame of 1443 bp. The gene encodes a 50 kDa polypeptide of 480 amino acids residues.
A single-nucleotide polymorphism (SNP) rs11200638 located in the HTRA1 promoter has been found in AMD (age-related macular degeneration) patients. The sequence change is located 512 basepairs upstream of the transcriptional start site of the HTRA1 gene (-512G/A) within a CpG island. It resides within the putative binding sites for transcription factors, AP2alpha (adaptor-related protein complex 2alpha) and SRF (serum response factor) (Yang et al., 2006; DeWan et al., 2006). Much debate exists regarding the functional significance of the HTRA1 promoter SNP and its influence on the HTRA1 gene expression. It was demonstrated that the HTRA1 promoter SNP is associated with the enhanced expression of the HTRA1 gene in lymphocytes and retinal pigment epithelium from AMD patients (Yang et al., 2006; DeWan et al., 2006). An et al. (2010) showed that increased expression of HTRA1 in retinal pigment epithelium cells form AMD patients harbouring homozygous risk genotype in comparison to wild type genotype. However, two independent studies did not show any influence of the risk variant on the HTRA1 expression in human lymphocytes and retina (Kanda et al., 2007; Chowers et al., 2008). Moreover, Kanda et al. (2010) did not find association between the rs11200638 SNP and steady-state expression of HTRA1 in retina of AMD patients. Results of reporter gene assays with HTRA1 promoter sequence provide no evidence for the influence of the rs1120638 SNP on the HTRA1 promoter activity (Friedrich et al., 2011). Friedrich et al. (2011) revealed also the presence of a Muller glia-specific cis-regulatory region located between -3550 and -2770 bp upstream of the HTRA1 transcription start site.

No pseudogenes have been identified.

HtrA1 protein belongs to the HtrA family of proteins. Members of the family are homologs of the HtrA protein from the bacterium Escherichia coli. They are evolutionarily conserved ATP-independent serine proteases, widely distributed from bacteria to humans. Structurally, the HtrA proteins are characterized by the presence of a trypsin-like protease domain and at least one PDZ domain at the C-terminus. The defence against cellular stresses inducing abberrations in protein structure is believed to be a general function of HtrAs (reviewed by Clausen et al., 2002). At least four human homologous HtrA proteins have been identified. They are involved in maintenance of mitochondrial homeostasis, apoptosis and cell signaling and disturbances in their functions may contribute to the development of several diseases including cancer, arthritis and neurodegenerative disorders (reviewed by Zurawa-Janicka et al., 2010). HTRA1 was originally identified as a gene downregulated in SV40-transformed fibroblasts (Zumbrunn and Trueb, 1996).

The HTRA1 gene encodes a polypeptide of 480 aa and of a mass of approximately 50 kDa.
The full-length HtrA1 protein contains a signal secretory peptide at the N-terminus (residues 1-22), a domain with homology to the insulin-like growth factor binding proteins (residues 25-111), a Kazal-type inhibitor motif (residues 115-135), and the evolutionarily conserved trypsin-like domain (residues 206-364) with the amino acid residues of serine protease catalytic triad (H220, D250, S328), and the PDZ domain (residues 382-473) at the C-terminus.
Under treatment of ovarian cancer cells with chemotherapeutic agents (cisplatin, paclitaxel) a removal of the N-terminal Mac25 domain was observed. The resulting product, mass of 35 kDa, expressed more active phenotype than the full-length protein (Chien et al., 2006). The proteolytic processing is believed to be an autocatalytic process since the catalytically inactive mutant did not undergo such modification.
The processed form of HtrA1, mass of 29 kDa was detected in CaSki cells (human cervical cancer line) and in 293T cells (human embryonic kidney line). The 29 kDa product was found to be a predominant active form in the nuclear fraction (Clawson et al., 2008).
The lower molecular weight products were also generated under overproduction of proteolytically active HtrA1 in heterologous expression systems (Hu et al., 1998).

HTRA1 is widely expressed in human tissues. High expression was detected in secretory breast epithelium, duct cells of liver, kidney tubules of cortex and in the glandular epithelium of proliferating endometrium. The highest expression was detected in mature layers of epidermis (De Luca et al., 2003).
It was demonstrated that HTRA1 expression in glandular and stromal cells increases gradually across menstrual cycle and reaches the maximum level at the mid- and late secretory phases (Nie et al., 2006). It was also reported that HTRA1 expression changes during pregnancy both in placental and endometrial cells. Up-regulation of HTRA1 was observed in endometrial glands and decidual cells during preparation of endometrium for embryo implantation and during the first trimester of placentation (Nie et al., 2006). However, the highest expression of HTRA1 was detected in placenta in the third trimester of gestation (De Luca et al., 2004). These data suggest an important role of HtrA1 in placenta development and function.
Changes in HTRA1 expression were observed in response to stress-inducing agents. Upon treatment of ovarian cancer cells expressing HTRA1 with the commonly used chemotherapeutics the HtrA1 protein level estimated by the Western blotting technique was increased (Chien et al., 2006).
Abnormal expression of the gene is associated with several diseases, including arthritis and many types of cancers.

HtrA1 is classified as a secreted protein. However, processed forms of HtrA1 have been found in the cytoplasm and in the nuclear fraction (Clawson et al., 2008; Chien et al., 2009; He et al., 2010).

HtrA1 acts as an ATP-independent serine protease.
HtrA1 has been shown to function as a regulator of TGF-beta signaling. HtrA1 binds to several members of the TGF-beta proteins family, including TGF-beta1, TGF-beta2, BMP2, BMP4, activin and Gdf5, and suppresses signal transduction mediated by these extracellular cytokines (Oka et al., 2004). It was demonstrated that the proteolytic activity of HtrA1 is indispensable for this inhibitory function (Oka et al., 2004). Recent studies showed also that TGF-beta1 is a substrate for HtrA1 in vitro (Launay et al., 2008). However, a hypothesis that degradation of TGF-beta proteins is the underlying mechanism of TGF-beta signaling regulation by HtrA1 needs further studies.
HtrA1 is involved in the programmed cell death, apoptosis. Treatment of the ovarian cancer cells with cisplatin or paclitaxel resulted in upregulation of HtrA1 expression. Under these conditions HtrA1 underwent autocatalytic activation resulting in activation of caspases 3 and 7 associated with apoptotic cell death. However, the mechanism of the process is unknown and needs to be elucidated (Chien et al., 2006).
HtrA1 is implicated in anoikis, a cell death induced by anchorage-dependent cells detaching from the surrounding extracellular matrix. Resistance to anoikis is a common feature of cancer cells and contributes to metastasis. HtrA1 regulates anoikis by modulating the EGFR/AKT pathway (He et al., 2010). HtrA1 binds to EGFR and inhibits EGRF/AKT pathway in a protease-dependent manner. It was demonstrated that HtrA1 expression was upregulated and underwent autocatalytic activation in response to loss of anchorage in suspended culture of ovarian cancer cells. Enhanced expression of HtrA1 in ovarian cancer cells suppressed EGFR/AKT signaling, which contributed to increased cell death, whereas downregulation of the gene attenuated anoikis in vitro and also promoted peritoneal dissemination of ovarian cancer cells in mouse model (He et al., 2010).

The HtrA1 protein is evolutionarily conserved among mammalian species. At the amino acid level the human HtrA1 shares a 98% identity with its orthologues from mouse, cow, rabbit, guinea pig (Hu et al., 1998) and hamster (Zurawa-Janicka et al., 2008).
At least three paralogs of HtrA1 have been identified in humans: HtrA2 (Omi), HtrA3 (PRSP) and HtrA4. HtrA1 protein shares the 54, 58 and 54% identity with HtrA2, HtrA3 and HtrA4 respectively. The homology between HtrA1 and its paralogs HtrA2, HtrA3 and HtrA4 reaches 75, 74 and 71%, respectively.

Two missense mutations G754A (the amino acid substitution A252T) and G889A (the amino acid substitution V297M) and two nonsense mutations C904T and C1108T (resulting in a stop codon at position 302 and 370, respectively) localized in exon 3 and 4, associated with the development of cerebral autosomal recessive arteriopathy with subcortical infarts and leukoencephalopathy (CARASIL) have been identified in the HTRA1 gene (Hara et al., 2009). The nonsense mutation C1108T resulted in the loss of protein product by nonsense-mediated mRNA decay. Three other mutations reduced the HtrA1 proteolytic activity in vitro and also failed to repress the TGF-beta signaling pathway (Hara et al., 2009).

Not known.

No breakpoints described so far.