Alternative titles; symbols
HGNC Approved Gene Symbol: CTSA
SNOMEDCT: 1197429000, 35691006;
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38) : 20:45,891,335-45,898,820 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | Brain small vessel disease 6 with leukoencephalopathy | 621394 | Autosomal dominant | 3 |
| Galactosialidosis | 256540 | Autosomal recessive | 3 |
Cathepsin A (protective protein) is a ubiquitously expressed multifunctional enzyme, with deamidase, esterase, and carboxypeptidase activities and a preference for substrates with hydrophobic amino acid residues at the P1-prime position. Association with CTSA, as part of the lysosomal multienzyme complex, is essential for stabilization of lysosomal beta-galactosidase (GLB1; 611458), as well as for activation of the lysosomal neuraminidase (NEU1; 608272) (summary by Seyrantepe et al., 2008). Cathepsin A also degrades endothelin-1 (EDN1; 131210), which plays a role in vasoconstriction and oligodendrocyte maturation (review by Finsterer et al., 2019).
Galjart et al. (1988) isolated a cDNA encoding the precursor of human CTSA, which they called protective protein. The deduced 480-amino acid precursor protein contains a 28-amino acid N-terminal signal sequence, followed by 298- and 154-amino acid domains that constitute the 32- and 20-kD subunits of the mature protein, respectively. The mature protein is a heterodimer of the 32- and 20-kD subunits held together by disulfide bridges. N-glycosylation sites are located within each of the subunits, at asn117 and asn305 (numbered after removal of the signal sequence), and these appeared to be glycosylated prior to maturation of the protein. Northern blot analysis detected a CTSA mRNA of about 2 kb in normal human fibroblasts.
Morreau et al. (1992) found that asn117 on the 32-kD subunit of protective protein acquired the mannose-6-phosphate necessary for lysosomal targeting of the molecule. Immunoelectron microscopy of transfected COS-1 cells revealed colocalization of protective protein with beta-galactosidase in lysosomes.
Mueller et al. (1984, 1986) used somatic cell mapping strategies and genetic complementation analysis to map the 2 genes required for expression of human neuraminidase. The structural gene was assigned to chromosome 10 and the gene for the 32-kD glycoprotein (CTSA) to chromosome 20.
Sips et al. (1985) concluded that whereas the structural gene for beta-galactosidase maps to chromosome 3, the beta-galactosidase protective protein maps to chromosome 22. However, using either a cDNA probe or a genomic probe for the human protective protein gene (PPGB) for in situ hybridization studies, Wiegant et al. (1991) found that the gene is located on 20q13.1. This assignment was confirmed by hybridization with whole chromosome DNA libraries. The work also confirmed the observation of Mueller et al. (1986) that the PPGB gene is the gene mutant in galactosialidosis.
Rothschild et al. (1993) identified and mapped new dinucleotide repeat polymorphisms associated with the PPGB and other loci on 20q in the region q12-q13.1. The PPGB marker was closely linked to D20S17, with a 2-point lod score of 50.53 at theta = 0.005.
To find the murine homolog of PPGB, Williamson et al. (1994) performed linkage analysis of 2 interspecific crosses and mapped the Ppgb gene to the region on distal mouse chromosome 2 that is conserved on human chromosome 20. Loci surrounding Ppgb are subject to parental imprinting; however, reverse transcription-PCR studies on mice with maternal duplication/paternal deficiency and its reciprocal showed that both parental alleles of Ppgb were expressed in the brain and kidney of 17.5- and 18.5-day-old embryos and newborn mice (Williamson et al., 1994). It seems, therefore, that Ppgb is not imprinted in the mouse.
Galjart et al. (1988) determined that a protective protein cDNA recognized a 2-kb mRNA in normal cells that was not evident in fibroblasts of an early infantile galactosialidosis patient (256540).
Strisciuglio et al. (1988) demonstrated by immunoprecipitation experiments a reduced amount of the 32-kD protective protein and a normal amount of its precursor in late infantile galactosialidosis fibroblasts, while neither of the 2 polypeptides were detectable in early infantile and juvenile/adult fibroblasts.
Kase et al. (1990) found that esterase and deamidase activities at pH 7.0 and carboxypeptidase activity at pH 5.7 were markedly low or deficient in 7 Japanese galactosialidosis patients. Since an enzyme with esterase, peptidase, and deamidase activities, purified from human platelets, was found to have an amino acid sequence identical to that deduced for protective protein, the results of Kase et al. (1990) were taken to indicate that the protective protein is multifunctional.
Using a number of criteria, Galjart et al. (1991) demonstrated that human protective protein is identical to cathepsin A. Mutagenesis of the catalytic residues ser150 and his429 abolished the cathepsin A-like activity of the protein, but had no affect on its intracellular routing, processing, and secretion. The secreted active-site mutant precursor retained its protective function and restored beta-galactosidase and neuraminidase activities of galactosialidosis fibroblasts. Galjart et al. (1991) concluded that the catalytic activity and protective function of cathepsin A are distinct.
To study the function of human protective protein, Morreau et al. (1992) generated a set of mutated protective protein cDNAs carrying targeted base substitutions. These mutants were either singly transfected into COS-1 cells or cotransfected together with wildtype human beta-galactosidase. Morreau et al. (1992) showed that all point mutations caused either a complete or partial retention of the protective protein precursor in the endoplasmic reticulum (ER). This abnormal accumulation led to degradation of the mutant proteins probably in this compartment. Wildtype protective protein and beta-galactosidase precursors interacted soon after synthesis in the ER. Mutated protective protein precursors retained in the ER or pre-Golgi complex interacted with and withheld normal beta-galactosidase molecules in the same compartments, thereby preventing their normal routing.
Lysosome-associated membrane protein-2A (LAMP2A; 309060) is a receptor for chaperone-mediated autophagy (CMA), which is normally activated by starvation. Degradation of LAMP2A is the rate-limiting step of CMA. Using lysosomes immunopurified from rat liver and cultured Ppca -/- mouse fibroblasts, Cuervo et al. (2003) showed that a lysosomal membrane-associated form of Ppca was responsible for Lamp2a degradation. Ppca cleaved Lamp2a at the boundary between the luminal and transmembrane domains. Reduced Ppca at the lysosomal membrane led to elevated Lamp2a levels and higher rates of CMA. The association of Ppca and Lamp2a was inhibited by protein substrates for CMA and increased by divalent cations, which promoted Ppca membrane localization. Lysosomes isolated from skin fibroblasts of 3 different galactosialidosis patients showed increased CMA activity, and supplementation of catalytically active PPCA to patient fibroblasts restored normal CMA activity.
Kleijer et al. (1996) surveyed 20 galactosialidosis patients with different clinical phenotypes. They tested cathepsin A activity in cultured fibroblasts derived from the patients and their obligate heterozygote parents. In 12 patients with the early infantile type of the disease, almost complete absence of cathepsin A activity was observed, whereas 8 patients with either delayed infantile or the juvenile/adult type had 2% to 5% residual activity. Highest levels (5%) were present in 2 patients with milder clinical manifestations and later onset of the disease. Heterozygous values for cathepsin A were reduced on average to half of normal levels. They showed that cathepsin A has considerable activity in chorionic villi and amniocytes and was deficient in amniocytes from a pregnancy with an affected fetus, indicating the relevance of cathepsin A assay for prenatal diagnosis of galactosialidosis.
Galactosialidosis
In 2 unrelated patients with the late infantile form of galactosialidosis (GSL; 256540), Zhou et al. (1991) identified a homozygous missense mutation in the CTSA gene (F412V; 613111.0001). Expression of the mutation in COS-1 cells substitution resulted in the synthesis of a mutant protein that lacked cathepsin A-like activity.
In a clinical and molecular analysis of 19 Japanese patients from 15 unrelated families with galactosialidosis, Takano et al. (1991) found only 2 cases with generalized and severe manifestations of neonatal onset; the other 17 cases had late onset of neurologic manifestations. All 17 late-onset patients had a splice site mutation in the CTLA gene resulting in a deletion of exon 7 (613111.0002).
Zhou et al. (1996) studied 8 patients with galactosialidosis who presented at different ages. All patients studied had PPCA mRNA. To identify the molecular lesions in the PPCA gene they used RT-PCR to amplify the entire coding sequence which was then sequenced. In the early-onset patients they detected 2 new mutations: val104 to met (613111.0009) and leu208 to pro (613111.0010). The second mutation present in one of the early-onset patients was gly411 to ser (613111.0011). A patient with juvenile/adult onset proved to be a compound heterozygote for a ser23-to-tyr mutation on one allele and a splice site mutation in intron 7 (613111.0002) on the other allele. The 5 patients with late infantile-onset galactosialidosis were genetically much more homogeneous, having either the phe412-to-val (613111.0001) or tyr221-to-asn (613111.0008) mutation. These mutations occurred either in the homozygous or compound heterozygous state and Zhou et al. (1996) considered them to be diagnostic for the late infantile phenotype. Zhou et al. (1996) determined that the main factor determining the clinical course in galactosialidosis patients is the lysosomal level of mutant PPCA. In 2 severely affected patients with early infantile onset, they identified 3 novel mutations, val104 to met, leu208 to pro, and gly411 to ser (613111.0011), that prevent the phosphorylation of the PPCA precursor and thereby its transport to the lysosome. Galactosialidosis patients with late infantile onset of disease had at least one allele that could be phosphorylated and transported to the lysosome. Zhou et al. (1996) noted that the met378-to-thr mutation (613111.0012), present in compound heterozygosity in one of the patients, represented the first example of a point mutation that generates a new asn-linked glycosylation site that is actually utilized. They noted further that the additional oligosaccharide chain likely affects the proper folding and compartmentalization of the mutant.
Brain Small Vessel Disease 6 with Leukoencephalopathy
In 11 patients spanning 2 generations of a Dutch family (family 1) with brain small vessel disease-6 with leukoencephalopathy (BSVD6; 621394), Bugiani et al. (2016) identified a heterozygous missense mutation in the CTSA gene (R325C; 613111.0016). A similarly affected father and daughter from another Dutch family (family 2) carried the same heterozygous mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. Haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 that encompassed 58 genes in affected individuals from families 1 and 2, suggesting a common ancestor. Carboxypeptidase activity in patient leukocytes was normal. Neuropathologic examination of 3 patients showed increased immunolabeling of CTSA in astrocytes with increased levels of the CTSA 54-kD precursor, increased EDN1 immunolabeling in astrocytes, increased numbers of oligodendrocyte precursors, and decreased levels of myelin basic protein (MBP; 159430).
In 2 unrelated patients, a 64-year-old Chinese woman (P1) and a 75-year-old Brazilian man of Italian origin (P2), with BSVD6, Budhdeo et al. (2022) identified heterozygosity for the R325C mutation in the CTSA gene. The mutations were found by targeted Sanger sequencing of the CTSA gene and focused exome sequencing, respectively, after variants in other genes associated with small vessel disease were excluded. Functional studies of the variant and studies of patient cells were not performed.
Seyrantepe et al. (2008) developed transgenic mice expressing a catalytically inactive form of mouse Catha due to a ser190-to-ala mutation. Transgenic mice were viable and fertile, appeared normal, and had a normal life span. Western blot and immunohistochemical analyses detected normal levels of the mutant protein, but no Catha activity was detected in kidney, liver, or lung. Transgenic mice developed no deficiency in Neu1 or beta-Gal. However, they showed significant loss of elastic fibers in elastin (ELN; 130160)-rich tissues, such as skin and elastic arteries, and an unusual enlargement of the alveolar sacs and thinning of the alveolar septae. Transgenic mice also showed elevated diastolic and systolic blood pressure and altered response to endothelin-1 (EDN1; 131240) that was associated with a reduced rate of endothelin-1 degradation compared with wildtype controls. Seyrantepe et al. (2008) concluded that CATHA acts as an endothelin-1-inactivating enzyme and is required for elastic fiber formation.
In 2 unrelated patients with the late-infantile form of galactosialidosis (GSL; 256540), Zhou et al. (1991) identified a T-to-G transversion at position 1324 in the protective protein gene, resulting in the substitution of valine for phenylalanine-412 (F412V) in the gene product. Expression in COS-1 cells of a protective protein cDNA with the base substitution resulted in the synthesis of a mutant protein that lacked cathepsin A-like activity. The newly made precursor was partially retained in the endoplasmic reticulum. The fraction that was transported to the lysosomes was degraded soon after proteolytic processing into the mature 2-chain form. Unlike the wildtype protein, the mutant precursor did not form homodimers. The patients, previously described by Chitayat et al. (1988) and Strisciuglio et al. (1990), were of Canadian and Italian origin, respectively. Although symptoms began in the first 2 years of life, the progression of the disease was slow and relatively mild with no signs of mental retardation.
Zhou et al. (1996) found this mutation in homozygous or compound heterozygous state and considered it and the tyr221-to-asn mutation (Y221N; 613111.0008) to be diagnostic for the late infantile-onset phenotype. They noted that the disorder in patients with the F412V mutation was clinically more severe than in those with the Y221N mutation.
Shimmoto et al. (1990) identified a splice mutation in the CTSA gene as the basis of the Japanese form of adult galactosialidosis (GSL; 256540): an A-to-G transition at a position 3 bp downstream of exon 7, resulting in skipping of that exon in mRNA. All 5 patients studied were found to be homozygous for this mutation.
In a Japanese child with galactosialidosis (GSL; 256540), Shimmoto et al. (1993) identified an A-to-G transition in exon 2 of the CTSA gene, resulting in a gln49-to-arg (Q49R) substitution. This mutation, like the W65R (613111.0004), S90L (613111.0005), and Y249N (613111.0007) mutations, was found in compound heterozygosity with the common intron 7 splice site mutation (613111.0002).
In a Japanese infant with galactosialidosis (GSL; 256540), Shimmoto et al. (1993) found compound heterozygosity for mutations in the CTSA gene: a T-to-C transition at nucleotide 193 in exon 2, resulting in a trp65-to-arg (W65R) substitution, and the intron 7 splice site mutation (613111.0002).
In a Japanese patient with galactosialidosis (GSL; 256540), Shimmoto et al. (1993) found a ser90-to-leu (S90L) amino acid substitution due to a change of nucleotides 268 and 269 in exon 3 from TC to CT in the CTSA gene, effectively a microinversion. The mutation was in compound heterozygosity with the common intron 7 splice site mutation (613111.0002).
Fukuhara et al. (1992) and Shimmoto et al. (1993) identified a 1184A-G transition in the CTSA gene, resulting in a tyr395-to-cys (Y395C) amino acid substitution, in galactosialidosis (GSL; 256540). The mutation was identified in compound heterozygosity with the common intron 7 splice site mutation (613111.0002). Shimmoto et al. (1993) concluded that the homozygous Y395C mutation, which is not accompanied by any expression of enzyme activity, is related to a clinically severe form of galactosialidosis; when combined with the splice site mutation, in which a small amount of normally spliced mRNA is produced, Y395C causes a phenotype of intermediate severity.
Like the intron 7 splice site mutation (613111.0002), the tyr249-to-asn (Y249N) mutation in the CTSA gene is frequent in Japanese patients with galactosialidosis (GSL; 256540) (Fukuhara et al., 1992). The mutation results from a T-to-A transversion at nucleotide 746 in exon 8. The mutation is accompanied by expression of a small amount of carboxypeptidase activity and, when present in compound heterozygosity with a mutation such as Y395C (613111.0006) without expression of any enzyme activity, it causes an intermediate phenotype.
In patients with galactosialidosis (GSL; 256540), Zhou et al. (1996) identified a tyr221-to-asn (Y221N) mutation in the CTSA gene, either in homozygous or compound heterozygous state. They considered this mutation and the phe412-to-val (F412V; 613111.0001) mutation to be diagnostic for the late infantile-onset phenotype, noting that patients who carried F412V had more severe clinical manifestations.
Zhou et al. (1996) identified a val104-to-met (V104M) mutation in the CTSA gene in a patient with early infantile-onset galactosialidosis (GSL; 256540). The mutation prevents the phosphorylation of the protein. No enzyme activity was detected in the lysosomes of this patient.
Zhou et al. (1996) identified a leu208-to-pro (L208P) mutation in the CTSA gene in a patient with early infantile-onset galactosialidosis (GSL; 256540). The mutation prevents phosphorylation of the protein. No enzyme activity was detected in the patient and death occurred in infancy.
Zhou et al. (1996) identified a gly411-to-ser (G411S) mutation in the CTSA gene in a patient with early infantile-onset galactosialidosis (GSL; 256540). The mutation prevents phosphorylation of the protein.
Zhou et al. (1996) identified a met378-to-ser (M378S) mutation in the CTSA gene in a patient with late infantile-onset galactosialidosis (GSL; 256540). This point mutation generates a new asn-linked glycosylation site, which is utilized. Increased glycosylation of the protein led to the occurrence of an immunoprecipitated protein of different electrophoretic mobility from that of the normal protein.
In a patient with the late infantile form of galactosialidosis (GSL; 256540), Richard et al. (1998) identified compound heterozygosity for 2 mutations in the CTSA gene: a 2-nucleotide deletion, 517_518delTT, and an intronic mutation, IVS8+9C-G (613111.0015), resulting in abnormal splicing and a 5-nucleotide insertion in the CTSA cDNA. Both mutations caused frameshifts and resulted in the synthesis of truncated cathepsin A proteins, which, as suggested by structural modeling, are incapable of dimerization, complex formation, and catalysis. However, study of the patient's cultured skin fibroblast extracts suggested that a small amount of cathepsin A mRNA was spliced normally and produced the wildtype protein. This may have contributed to the relatively mild phenotype of the patient. The patient was an 18-year-old woman whose father and mother were healthy and nonconsanguineous, of Polish and Italian-Canadian origin, respectively. At 7 months of age she had shown mild hepatosplenomegaly, respiratory obstruction, bilateral lamellar cataracts, and bone changes including atypical punctate calcifications of the tarsal region. She walked at 21 months, was fitted with hearing aids at 3 years of age, and spoke with good sentences at the age of 4.5 years. She retained functional vision despite mild myopia, lamellar cataracts, mild corneal opacification and bilateral macular cherry red spots, perifoveal hypopigmentation, and tortuosity of the retinal arteries. Progressive hyperreflexia was first noted at 3 years of age and intention myoclonus at 9 years of age. At age 12, CT scan showed cerebral atrophy. EEG at 16 years of age showed epileptic activity, although she had had no clinical seizures.
In a 7-year-old Arab girl with late-infantile galactosialidosis (GSL; 256540), Takiguchi et al. (2000) identified homozygosity for a 1357A-G transition in the CTSA gene, resulting in a lys453-to-glu (K453E) substitution. The girl was noted to have coarse facies at birth. At age 7 years, she was noted to have hepatosplenomegaly and her mental age was estimated to be 4 years. Neurologic examination was negative. Macular cherry red spots and vacuolated lymphocytes were observed. A skeletal survey showed mild changes of dysostosis multiplex, including a 'J'-shaped sella and thickening of the vertebrae. Lysosomal enzyme assays showed a combined deficiency of cathepsin A, beta-galactosidase, and neuraminidase activities. Northern blot analysis showed that the patient had a normal amount of CTSA mRNA. Studies showed that the precursor CTSA was synthesized but not processed to the mature form. In addition, the K453E mutation was located at the dimer interface of PPCA and reduced the hydrogen bond formation in the dimer, possibly resulting in instability of the PPCA dimer.
For discussion of the intronic mutation in the CTSA gene (IVS8+9C-G) that was found in compound heterozygous state in a patient with late infantile galactosialidosis (GSL; 256540) by Richard et al. (1998), see 613111.0013.
In 11 patients spanning 2 generations of a Dutch family (family 1) with brain small vessel disease-6 with leukoencephalopathy (BSVD6; 621394), Bugiani et al. (2016) identified a heterozygous c.973C-T transition (c.973C-T, NM_000308.2) in the CTSA gene, resulting in an arg325-to-cys (R325C) substitution. A similarly affected father and daughter from another Dutch family (family 2) carried the same heterozygous mutation. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. Haplotype analysis identified a shared region of 1,145 kb on chromosome 20q13 that encompassed 58 genes in affected individuals from families 1 and 2, suggesting a common ancestor. Carboxypeptidase activity in patient leukocytes was normal.
In 2 unrelated patients, a 64-year-old Chinese woman (P1) and a 75-year-old Brazilian man of Italian origin (P2), with BSVD6, Budhdeo et al. (2022) identified heterozygosity for the R325C mutation in the CTSA gene. The mutations were found by targeted Sanger sequencing of the CTSA gene and focused exome sequencing, respectively, after variants in other genes associated with small vessel disease were excluded. Functional studies of the variant and studies of patient cells were not performed.
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