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HTRA SERINE PEPTIDASE 1; HTRA1

HTRA SERINE PEPTIDASE 1; HTRA1

Alternative titles; symbolsHtrA, E. COLI, HOMOLOG OF; HTRAPROTEASE, SERINE, 11; PRSS11HGNC Approved Gene Symbol: HTRA1Cytogenetic location: 10q26.13 Genomic ...

Alternative titles; symbols

  • HtrA, E. COLI, HOMOLOG OF; HTRA
  • PROTEASE, SERINE, 11; PRSS11

HGNC Approved Gene Symbol: HTRA1

Cytogenetic location: 10q26.13 Genomic coordinates (GRCh38): 10:122,461,552-122,514,906 (from NCBI)

▼ Description
HTRA1 is a member of the HTRA (high temperature requirement) family of serine proteases first identified in bacteria. These proteases are characterized by a highly conserved trypsin (see 276000)-like serine protease domain and at least 1 C-terminal PDZ domain. HTRA1 also contains an insulin-like growth factor-binding protein (see 146730) domain and a Kazal-type serine protease inhibitor (see 167790) motif at its N terminus. HTRA1 can degrade several extracellular matrix components and plays a role in cancer and degenerative diseases (summary by Grau et al., 2006).

▼ Cloning and Expression
Zumbrunn and Trueb (1996) cloned the cDNA for a human protein, termed L56 by them, that seemed to be part of the IGF signaling system. The predicted protein encodes a 480-amino acid polypeptide with a molecular mass of 51 kD. Zumbrunn and Trueb (1996) found that PRSS11 contains a secretory signal sequence, an IGFBP-binding domain, and a serine protease domain. The serine protease domain is most similar to certain bacterial serine proteases. By Northern blot analysis, Zumbrunn and Trueb (1996) showed that PRSS11 is expressed in a variety of human tissues, with strongest expression in placenta.

Hu et al. (1998) also cloned PRSS11. The deduced 480-amino acid protein is 98% identical to the cow, guinea pig, and rabbit proteins. It contains an N terminus homologous to MAC25 (IGFBP7; 602867) with a conserved Kazal-type serine protease inhibitor motif, as well as a C-terminal PDZ domain. Semiquantitative RT-PCR and immunoblot analyses showed an approximately 7-fold increase of PRSS11 in osteoarthritis cartilage compared with controls. Functional and mutational analyses indicated that PRS11 is a serine protease dependent on the presence of a serine at position 328.

▼ Gene Function
Chien et al. (2004) found that HTRA1 was downregulated in 59% of primary ovarian tumors and observed high frequencies for LOH at microsatellite markers near HTRA1 on 10q26. Antisense transfection studies showed that downregulation of HTRA1 promoted anchorage-independent growth, while exogenous expression induced cell death. Chien et al. (2004) suggested that HTRA1 may be a tumor suppressor involved in promoting serine-protease-mediated cell death.

Chien et al. (2006) demonstrated that downregulation of HTRA1 in ovarian cancer cell lines attenuated cisplatin- and paclitaxel-induced cytotoxicity, whereas forced expression of HTRA1 enhanced chemotherapeutic cytotoxicity. Patients with ovarian epithelial (167000) or gastric (137215) tumors expressing higher levels of HTRA1 showed a significantly higher response rate to chemotherapy than those with lower levels of HTRA1 expression. Chien et al. (2006) suggested that loss of HTRA1 in ovarian and gastric cancers may contribute to in vivo chemoresistance.

Using ELISA, Grau et al. (2006) found that expression of HTRA1 was upregulated in synovial fluid from both osteoarthritis (OA; see 165720) and rheumatoid arthritis (RA; see 180300) patients compared with normal human fluid. HTRA1 was also highly expressed in and secreted by cultured OA and RA synovial fibroblasts, but not by normal human foreskin fibroblasts. Recombinant human HTRA1 lacking the N-terminal IGF-binding and serine protease inhibitor domains, representing an autoproteolytically processed form, degraded purified human fibronectin (FN1; 135600) into several fragments. Synovial fibroblasts exposed to these fragments subsequently upregulated mRNA expression and secretion of the matrix metalloproteases MMP1 (120353) and MMP3 (185250). Inhibition of HTRA1 abrogated fibronectin fragment formation and MMP upregulation. Grau et al. (2006) concluded that HTRA1 can contribute to destruction of extracellular matrix through both direct and indirect mechanisms.

Using quantitative RT-PCR analysis, Tiaden et al. (2012) found that expression of HTRA1 was upregulated in degenerating patient intervertebral discs (IVDs), and expression of HTRA1 positively correlated with disease severity. Western blot analysis detected both full-length and processed HTRA1 species at apparent molecular masses of 50 and 42 kD, respectively. The 42-kD form was found in patient IVD samples only, and the amount increased with severity of disease. Cultured IVD fibroblasts exposed to recombinant HTRA1 lacking the N-terminal domains responded by increasing their expression of MMP1 and MMP3, as well as a specific subset of other matrix proteases. IVD cells exposed to HTRA1-generated fibronectin fragments also showed upregulation and activation of MMPs. This effect was not observed in cells exposed to inactivated truncated HTRA1 or following HTRA1 inhibition.

Akhatib et al. (2013) found that chondroadherin (CHAD; 602178) was intact in normal human IVDs, but that it was fragmented in adults with IVD degeneration and in damaged discs in adolescent idiopathic scoliosis. The amount of fragmented CHAD correlated with severity of disease, but in all cases, CHAD was specifically cleaved between ile80 and tyr81. Akhatib et al. (2013) found that the CHAD cleavage site generated by HTRA1 was identical to that present in situ. HTRA1 protein was observed in both degenerate adult and adolescent scoliotic samples and was elevated compared with normal disc samples. Akhatib et al. (2013) concluded that HTRA1 plays a role in CHAD fragmentation in degenerating disc diseases.

▼ Mapping
Using fluorescence in situ hybridization, Zumbrunn and Trueb (1997) mapped the PRSS11 gene to chromosome 10q25.3-q26.2.

▼ Molecular Genetics
Age-Related Macular Degeneration 7

From a cohort of Southeast Asians in Hong Kong, DeWan et al. (2006) identified 96 patients who had been previously diagnosed with wet age-related macular degeneration (ARMD7; 610149) and 138 matched control individuals who were ARMD-free. Because the putative locus on 10q26 in which a previously identified SNP with significant association with ARMD had been removed from GenBank (see LOC387715, 611313), DeWan et al. (2006) sequenced the entire local genomic region, including promoters, exons, and intron-exon junctions of PLEKHA1 (607772) and HTRA1, in search of the functional variant. They found that 1 SNP in the promoter region of HTRA1, rs11200638 (602194.0001), located 512 base pairs upstream of the HTRA1 putative transcriptional start site and 6,096 basepairs downstream of the previously identified SNP, exhibited a complete linkage disequilibrium pattern with the previously identified SNP. The SNP rs11200638 resides within putative binding sites for the transcription factors adaptor-related protein complex 2-alpha (AP2-alpha; 107580) and serum response factor (SRF; 600589). Preliminary results showed higher HRTA1 expression correlated with the risk (AA) compared with the wildtype (GG) genotype in in vitro transfection assays.

Yang et al. (2006) independently identified the same SNP in the HTRA1 promoter region as causative of age-related macular degeneration in a Caucasian cohort in Utah. The authors suggested that the estimated population-attributable risk for the SNP is 49.3%. Consistent with an additive effect, the estimated population-attributable risk from a joint model with CFH Y402H (134370.0008) (i.e., for a risk allele at either locus) is 71.4%.

Contrary to the findings of DeWan et al. (2006) and Yang et al. (2006), Kanda et al. (2007) found that rs11200638 had no significant impact on HTRA1 promoter activity in 3 different cells lines, and that HTRA1 mRNA expression exhibited no significant change between control and ARMD retinas. By evaluating 45 tag SNPs spanning the HTRA1, PLEKHA1, and LOC387715 in 466 cases of ARMD and 280 controls, they determined that rs10490924 in the LOC387715 gene alone, or a variant in strong linkage disequilibrium, could explain the bulk of the association between the 10q26 region and ARMD, whereas rs11200638 in the HTRA1 gene could not. They concluded that the association of the HTRA1 polymorphism with ARMD susceptibility was likely to be indirect.

In a resequencing study of the locus on chromosome 10q26 associated with ARMD, Fritsche et al. (2008) identified an insertion/deletion polymorphism in the LOC387715 gene (611313.0002) that was highly associated with ARMD and that generated an unstable mRNA. The authors also confirmed association of the SNP rs11200638 and identified an intronic SNP that they considered 'unlikely to exert consequences on gene function.'

Autosomal Recessive Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142) is a nonhypertensive cerebral small vessel arteriopathy characterized by alopecia, spondylosis, and progressive motor dysfunction and dementia. By linkage analysis and fine mapping, followed by candidate gene sequencing, in 6 consanguineous Japanese families with CARASIL, Hara et al. (2009) identified 4 different homozygous mutations in the HTRA1 gene (602194.0002-602194.0005). The mutant proteins were unable to repress TGF-beta (190180) activity, and increased expression TGFB1 was observed in the tunica media of affected small arteries. These findings indicated that CARASIL is a disease associated with dysregulation of TGF-beta signaling.

Autosomal Dominant Cerebral Arteriopathy with Subcortical Infarcts and Leukoencephalopathy Type 2

Using whole-exome sequencing to identify candidate genes in a family with autosomal dominant small vessel disease (cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2; CADASIL2; 616779) in which known small vessel disease genes had been excluded, Verdura et al. (2015) identified heterozygosity for a missense mutation (R166L; 602194.0001) in the HTRA1 gene in all affected members. The mutation was not present in the 1000 Genomes Project or the EVS databases and was predicted to be deleterious by in silico tools. The authors subsequently used high-throughput multiplex polymerase chain reaction and next-generation sequencing to screen all candidate genes in 201 unrelated probands from families with small vessel disease of unknown etiology. Ten of the probands (4.97%) harbored a heterozygous HTRA1 mutation predicted to be damaging. There was a highly significant difference in the number of likely deleterious variants in cases compared to controls (p = 4.2 x 10(-6); odds ratio = 15.4; 95% CI = 4.9 - 45.5), strongly suggesting causality. In vitro activity analysis of HTRA1 mutants demonstrated a loss-of-function effect.

▼ Animal Model
Francis et al. (2008) genotyped 137 unrelated rhesus macaques, 81 with and 56 without macular drusen, and identified a variant in the Htra1 gene that was significantly associated with affected status. Functional analysis of the polymorphic variant showed a 2-fold increase in gene expression, supporting a role in pathogenesis. Francis et al. (2008) stated that this was the first evidence that humans and macaques share the same genetic susceptibility factors for common complex disease.

Zhang et al. (2012) found that Htra1 -/- mice showed reduced retinal vasculature compared with wildtype. Knockout of Htra1 significantly upregulated expression of Gdf6 (601147) and downregulated expression of Vegf (192240) in retinal pigment epithelia. Increased levels of phosphorylated Smad1 (601595), Smad5 (603110), and Smad8 (SMAD9; 603295), which are downstream effectors of Gdf6 signaling, were present in Htra1 -/- brain. Zhang et al. (2012) concluded that HTRA1 regulates angiogenesis via TGF-beta signaling by GDF6.

▼ ALLELIC VARIANTS ( 12 Selected Examples):

.0001 MACULAR DEGENERATION, AGE-RELATED, 7, SUSCEPTIBILITY TO
MACULAR DEGENERATION, AGE-RELATED, NEOVASCULAR TYPE, SUSCEPTIBILITY TO, INCLUDED
HTRA1, -512G-A (rs11200638)
DeWan et al. (2006) identified a SNP (rs11200638) for which homozygosity for the AA genotype results in a 10-fold (confidence intervals 4.38 to 22.82) increased risk of wet age-related macular degeneration (see ARMD7, 610149) in a Southeast Asian population identified in Hong Kong. Yang et al. (2006) independently identified this variant as conferring risk in a Caucasian cohort from Utah.

Mori et al. (2007) found a significant association between the -512A allele and ARMD among 123 Japanese patients and 133 Japanese controls. The frequency of the risk A allele was 0.577 and 0.380 in patients and controls, respectively, yielding an odds ratio of 2.23 (p = 7.75 x 10(-6)). The results were more significant in a subset of 104 Japanese patients with wet ARMD (p = 5.96 x 10(-7)). The association was significant in both nonsmokers and smokers, and was more significant in nonsmokers.

Fritsche et al. (2008) identified rs11200638 as 1 of 6 highly correlated risk alleles residing on a single risk haplotype within the 23.3-kb region on chromosome 10q26 associated with age-related macular degeneration (P = 6.9 x 10(-29)).

In a matched sample set from the Age-Related Eye Disease Study (AREDS) cohort involving 424 patients with ARMD and 215 without ARMD acting as controls, Bergeron-Sawitzke et al. (2009) confirmed association between ARMD and rs11200638, with both the GA (OR, 3.2; p = 8.7 x 10(-9)) and AA (OR, 9.1; p = 6.4 x 10(-10)) genotypes. Bergeron-Sawitzke et al. (2009) noted that rs11200638 is in strong linkage disequilibrium with the rs10490924 SNP (611313.0001) in the LOC387715 gene that has also been associated with ARMD.

.0002 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, ARG370TER
In a Japanese woman with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Hara et al. (2009) identified a homozygous 1108C-T transition in the HTRA1 gene, resulting in an arg370-to-ter (R370X) substitution. The parents were consanguineous. Studies in patient fibroblasts showed that the mutation resulted in nonsense-mediated mRNA decay and no protein production.

.0003 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, ARG302TER
In affected members of 2 unrelated Japanese families with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Hara et al. (2009) identified a homozygous 904C-T transition in the HTRA1 gene, resulting in an arg302-to-ter (R302X) substitution. Both families were consanguineous. In vitro functional expression studies showed that the R302X mutant had 21 to 50% normal protease activity and was unable to repress TGF-beta activity.

.0004 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, VAL297MET
In affected members of 2 unrelated Japanese families with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Hara et al. (2009) identified a homozygous 889G-A transition in the HTRA1 gene, resulting in a val297-to-met (V297M) substitution. Both families were consanguineous. In vitro functional expression studies showed that the V297M mutant had 21 to 50% normal protease activity and was unable to suppress TGF-beta activity.

.0005 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, ALA252THR
In 2 sibs with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), born of consanguineous Japanese parents, Hara et al. (2009) identified a homozygous 754G-A transition in the HTRA1 gene, resulting in an ala252-to-thr (A252T) substitution. In vitro functional expression studies showed that the A252T mutant had 21 to 50% normal protease activity and was unable to repress TGF-beta activity.

.0006 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, GLY295ARG
In a Caucasian man of Spanish descent with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Mendioroz et al. (2010) identified a homozygous 883G-A transition in exon 4 of the HTRA1 gene, resulting in a gly295-to-arg (G295R) substitution in a highly conserved residue in the binding pocket of the protease domain. Each parent was heterozygous for the mutation, which was not found in 80 controls. The patient presented at age 34 years with unsteady gait, urinary urgency, and slurred speech. He had had alopecia since before age 18 years. The disorder was progressive, and the patient subsequently developed cognitive impairment with dysexecutive syndrome, pseudobulbar syndrome, and tetraparesis. Brain MRI showed diffuse leukoencephalopathy, lacunar infarcts, and microbleeds. The patient's mother, who was heterozygous for the mutation, had nonhypertensive leukoencephalopathy.

.0007 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, ALA321THR
In a 29-year-old Romanian woman with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142), Bianchi et al. (2014) identified compound heterozygous mutations in the HTRA1 gene: a c.961G-A transition in exon 4, resulting in an ala321-to-thr (A321T) substitution at a highly conserved residue in the serine protease domain, and a 1-bp deletion (c.126delG; 602194.0007) in exon 1, resulting in a frameshift (Glu42fs) and premature termination at position 214. The missense mutation was inherited from the father and the truncating mutation from the mother. The mutations, which were found by direct sequencing of the HTRA1 gene, were not present in the dbSNP (build 137) or 1000 Genomes Project databases, or in 320 control chromosomes. The father showed mild supratentorial leukoencephalopathy and the mother showed diffuse infra- and supratentorial leukoencephalopathy, but both parents were neurologically normal, suggesting that the carrier condition may be paucisymptomatic. Functional studies of the variants were not performed.

.0008 CEREBRAL ARTERIOPATHY, AUTOSOMAL RECESSIVE, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY
HTRA1, 1-BP DEL, 126G
For discussion of the c.126delG mutation in the HTRA1 gene that was found in compound heterozygous state in a patient with autosomal recessive cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL; 600142) by Bianchi et al. (2014), see 602194.0007.

.0009 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2
HTRA1, ARG166LEU
By whole-exome sequencing of 3 affected individuals (2 sibs and a first cousin) in a family (F1) referred for stroke and/or cognitive impairment associated with diffuse white matter hyperintensities (CADASIL2; 616779), Verdura et al. (2015) identified a heterozygous c.497G-T transversion (c.497G-T, NM_002775.4) in exon 2 of the HTRA1 gene, resulting in an arg166-to-leu (R166L) substitution. Verdura et al. (2015) performed a BSA assay, which showed loss of activity of the R166L mutant compared to controls.

.0010 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2
HTRA1, ALA173PRO
Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, Verdura et al. (2015) sequenced the HTRA1 gene in 201 unrelated probands with familial small vessel disease of unknown etiology and identified a c.517G-C transversion (c.517G-C, NM_002775.4) in exon 2, resulting in an ala173-to-pro (A173P) substitution, in a 72-year-old female proband (family F2) with a history of hypertension, balance impairment, cognitive impairment, gait disturbance, confluent white matter hyperintensities, multiple lacunar infarcts, and dilated perivascular spaces with a typical status cribrosum (CADASIL2; 616779). Verdura et al. (2015) performed a BSA assay, which showed loss of activity of the A173P mutant compared to controls.

.0011 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2
HTRA1, SER284ARG
Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, Verdura et al. (2015) sequenced the HTRA1 gene in 201 unrelated probands with a familial small vessel disease of unknown etiology and identified a c.852C-A transversion (c.852C-A, NM_002775.4) in exon 4, resulting in a ser284-to-arg (S284R) substitution, in a 49-year-old female proband (family F3) with a history of hypertension, headache, cognitive impairment, gait disturbance, confluent white matter hyperintensities, multiple lacunar infarcts, and dilated perivascular spaces with a typical status cribrosum (CADASIL2; 616779). Verdura et al. (2015) performed a BSA assay, which showed partial loss of activity of the S284R mutant compared to controls.

.0012 CEREBRAL ARTERIOPATHY, AUTOSOMAL DOMINANT, WITH SUBCORTICAL INFARCTS AND LEUKOENCEPHALOPATHY, TYPE 2
HTRA1, IVS4AS, G-A, -1
Using high-throughput multiplex polymerase chain reaction and next-generation sequencing, Verdura et al. (2015) sequenced the HTRA1 gene in 201 unrelated probands with a familial small vessel disease of unknown etiology and identified a c.973-1G-A transition (c.973-1G-A, NM_002775.4) in intron 4, resulting in a protein change of Tyr325_Leu335del, in a 66-year-old female proband (family F6) with a history of hypertension, stroke, transient ischemic attacks, confluent white matter hyperintensities, multiple lacunar infarcts, microbleeds and dilated perivascular spaces with a typical status cribrosum (CADASIL2; 616779).

Tags: 10q26.13