HGNC Approved Gene Symbol: CTSD
SNOMEDCT: 720830009;
Cytogenetic location: 11p15.5 Genomic coordinates (GRCh38) : 11:1,752,755-1,763,927 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11p15.5 | Ceroid lipofuscinosis, neuronal, 10 | 610127 | Autosomal recessive | 3 |
Cathepsin D (EC 3.4.23.5) is one of the lysosomal proteinases. It is ubiquitously expressed and is involved in proteolytic degradation, cell invasion, and apoptosis (Steinfeld et al., 2006).
Faust et al. (1985) cloned human cathepsin D from a kidney cDNA library. The cDNA encodes a 412-amino acid protein with 20 and 44 amino acids in a pre- and prosegment, respectively.
By study of somatic cell hybrids, Hasilik et al. (1982) assigned the structural gene for cathepsin D to chromosome 11 and specifically to the region 11pter-11q12. By somatic cell hybrid deletion mapping and in situ hybridization, Qin et al. (1987) mapped CTSD to 11p15. Henry et al. (1989) likewise mapped CTSD to 11p15 using somatic cell hybrids with specific deletions. CTSD mapped distal to a breakpoint at 11p15.4.
Proteolytic maturation of cathepsin D takes place during its transport from the trans-Golgi network (TGN) to lysosomes. Mardones et al. (2007) found that a protein complex made up of p56 (CCDC91; 617366) and the clathrin adaptors GGA1 (606004), GGA2 (606005), and GGA3 (606006) participated in clathrin (see 118955)-dependent movement of transport carrier vesicles between the TGN and lysosomes. Knockdown of any of these components inhibited maturation of cathepsin D from the pro-form, through an intermediate, to the mature enzyme, with knockdown of clathrin having the most dramatic effect.
In a mouse model of neuronopathic Gaucher disease (230900) in which glucocerebrosidase deficiency is limited to neural and glial progenitor cells, Vitner et al. (2010) showed significant changes in the levels and distribution of cathepsins in brain. Cathepsin mRNA expression, activity, and protein levels were significantly elevated, with the time course of the increase correlating with the progression of disease severity. Significant changes in cathepsin D distribution in the brain were detected, with cathepsin D elevated in areas where neuronal loss, astrogliosis, and microgliosis were observed. Cathepsin D elevation was greatest in microglia and astrocytes, and also in neurons in a manner consistent with its release from the lysosome to the cytosol. Ibubrofen treatment significantly reduced cathepsin D mRNA levels in the cortex of these mice, and cathepsin levels were also altered in mouse models of other sphingolipidoses. Vitner et al. (2010) suggested the involvement of cathepsins in the neuropathology of neuronal forms of Gaucher disease and of other lysosomal storage diseases, and hypothesized a crucial role for reactive microglia in neuronal degeneration in these diseases.
Using purified recombinant human HEBP1 (605826), Devosse et al. (2011) found that CTSD cleaved HEBP1 to produce the functional F2L peptide. Microarray analysis of human tissues showed that CTSD and HEBP1 were highly coexpressed in human liver, kidney, and spleen, consistent with a role of CTSD in HEBP1 processing in vivo.
In mice and sheep, cathepsin D deficiency causes a fatal neurodegenerative disease. Steinfeld et al. (2006) reported a novel disorder in a child with early blindness and progressive psychomotor disability (CLN10; 610127) who was compound heterozygous for missense mutations in the CTSD gene (F229I, 116840.0001 and W383C, 116840.0002). The mutations caused markedly reduced proteolytic activity and a diminished amount of cathepsin D in the patient's fibroblasts. Expression of cathepsin D mutants in fibroblasts of Ctsd -/- mice revealed disturbed posttranslational processing and intracellular targeting for W383C and diminished maximal enzyme velocity for F229I. Computer modeling suggested larger structural alterations for W383C than for F229I.
In a Pakistani infant with severe congenital CLN10, Siintola et al. (2006) identified a homozygous null mutation (116840.0003) in the CTSD gene.
In 4 sibs, born of consanguineous Somali parents, with juvenile-onset CLN10, Hersheson et al. (2014) identified a homozygous missense mutation in the CTSD gene (G149V; 116840.0004). The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. An unrelated Somali boy with a similar disorder carried a different homozygous missense mutation (R399H; 116840.0005). In both families, patient fibroblasts showed significantly decreased cathepsin D activity (11% of control values).
Tyynela et al. (2000) identified a mutation in ovine cathepsin D that accounts for congenital ovine neuronal ceroid lipofuscinosis (CONCL). In this disorder, which is transmitted as an autosomal recessive, newborn lambs are weak, trembling, and unable to rise and support their bodies. However, they are able to vocalize, support their heads, and to suckle if bottle-fed. At autopsy, the brains of affected lambs are strikingly small. The deep layers of the cerebral cortex show pronounced neuronal loss, reactive astrocytosis, and infiltration of macrophages. There is severe degeneration of hippocampal pyramidal neurons. The cerebellum is less affected. The basal ganglia, thalamus, and brainstem are relatively spared. Visceral tissues are unaffected. These animals have normal palmitoyl protein thioesterase activity, indicating that the molecular bases of human infantile neuronal ceroid lipofuscinosis (see 256730) and CONCL are distinct. As the pathology of CONCL suggested a lysosomal storage disease, Tyynela et al. (2000) measured a range of lysosomal enzyme activities and found strikingly deficient cathepsin D activity, which was about 40% of normal in heterozygous lambs. A G-to-A transition at nucleotide 934 was found in homozygosity in all affected animals. This mutation results in a substitution of an asparagine for aspartate at the codon corresponding to human asp295 of cathepsin D and asp215 of pepsin (see 169700). This residue is conserved among all aspartyl proteinases and represents 1 of the 2 aspartate residues that are essential for catalytic function of these proteins.
In a patient with cathepsin D-deficient neuronal ceroid lipofuscinosis (CLN10; 610127), Steinfeld et al. (2006) found compound heterozygosity for mutations in the CTSD gene. On the maternal allele, a 6517T-A transversion in exon 5 resulted in a phe229-to-ile (F229I) substitution. The paternal allele carried a 10267G-C transversion in exon 9, resulting in a trp383-to-cys substitution (W383C; 116840.0002). The F229I substitution in the cathepsin D precursor protein corresponds to F165I in the mature protein. Phe229 belongs to a group of 15 amino acids that are strictly conserved among the members of the pepsin family of peptidases. The W383C substitution in the cathepsin D precursor protein corresponds to W319C in the mature protein. Trp383 is conserved among all 12 human pepsin peptidases and nearly all other mammalian members of this family but is not conserved within pepsin peptidases from more distantly related species.
For discussion of the trp383-to-cys (W383C) mutation in the CTSD gene that was found in compound heterozygous state in a patient with cathepsin D-deficient neuronal ceroid lipofuscinosis (CLN10; 610127) by Steinfeld et al. (2006), see 116840.0001.
In a Pakistani infant with congenital neuronal ceroid lipofuscinosis-10 (CLN10; 610127), Siintola et al. (2006) identified homozygosity for a 1-bp duplication (764dupA) in exon 6 of the CTSD gene, resulting in a premature stop codon (tyr255-to-ter; Y255X), truncation of the protein by 158 amino acids, and deletion of the active site aspartic acid residue at position 295. The mutation was not identified in 550 control chromosomes. In vitro functional expression studies in baby hamster kidney cells showed that the mutant protein had no enzymatic activity. The unaffected father was heterozygous for the mutation; DNA from the mother, who was the first cousin of the father, was not available. There were 2 other affected brothers in the same family, but their DNA was also not available. The 3 boys died at ages 10, 1, and 4 days of age, after demonstrating intractable seizures, spasticity, and apnea immediately after birth.
In 4 sibs, born of consanguineous Somali parents, with neuronal ceroid lipofuscinosis-10 (CLN10; 610127), Hersheson et al. (2014) identified a homozygous mutation in exon 4 of the CTSD gene, resulting in a gly149-to-val (G149V) substitution at a highly conserved residue. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed significantly decreased cathepsin D activity (11% of control values). The patients presented at around age 15 years with cerebellar ataxia and retinitis pigmentosa, which progressed to significant motor impairment and cognitive decline. Two patients died in their thirties.
In a boy, born of consanguineous Somali parents, with neuronal ceroid lipofuscinosis-10 (CLN10; 610127), Hersheson et al. (2014) identified a homozygous mutation in exon 9 of the CTSD gene, resulting in an arg399-to-his (R399H) substitution at a highly conserved residue. Patient fibroblasts showed significantly decreased cathepsin D activity (11% of control values). The patient had juvenile onset of the disorder at age 8 years.
Devosse, T., Dutoit, R., Migeotte, I., De Nadai, P., Imbault, V., Communi, D., Salmon, I., Parmentier, M. Processing of HEBP1 by cathepsin D gives rise to F2L, the agonist of formyl peptide receptor 3. J. Immun. 187: 1475-1485, 2011. [PubMed: 21709160] [Full Text: https://doi.org/10.4049/jimmunol.1003545]
Faust, P. L., Kornfeld, S., Chirgwin, J. M. Cloning and sequence analysis of cDNA for human cathepsin D. Proc. Nat. Acad. Sci. 82: 4910-4914, 1985. [PubMed: 3927292] [Full Text: https://doi.org/10.1073/pnas.82.15.4910]
Hasilik, A., von Figura, K., Grzeschik, K.-H. Assignment of a gene for human cathepsin D to chromosome 11. (Abstract) Cytogenet. Cell Genet. 32: 284 only, 1982.
Henry, I., Puech, A., Antignac, C., Couillin, P., Jeanpierre, M., Ahnine, L., Barichard, F., Boehm, T., Augereau, P., Scrable, H., Rabbitts, T. H., Rochefort, H., Cavenee, W., Junien, C. Subregional mapping of BWS, CTSD, MYOD1, and a T-ALL breakpoint in 11p15. (Abstract) Cytogenet. Cell Genet. 51: 1013 only, 1989.
Hersheson, J., Burke, D., Clayton, R., Anderson, G., Jacques, T. S., Mills, P., Wood, N. W., Gissen, P., Clayton, P., Fearnley, J., Mole, S. E., Houlden, H. Cathepsin D deficiency causes juvenile-onset ataxia and distinctive muscle pathology. Neurology 83: 1873-1875, 2014. [PubMed: 25298308] [Full Text: https://doi.org/10.1212/WNL.0000000000000981]
Mardones, G. A., Burgos, P. V., Brooks, D. A., Parkinson-Lawrence, E., Mattera, R., Bonifacino, J. S. The trans-Golgi network accessory protein p56 promotes long-range movement of GGA/clathrin-containing transport carriers and lysosomal enzyme sorting. Molec. Biol. Cell 18: 3486-3501, 2007. [PubMed: 17596511] [Full Text: https://doi.org/10.1091/mbc.e07-02-0190]
Qin, S., Nakai, H., Byers, M. G., Eddy, R. L., Haley, L. L., Henry, W. M., Wang, X., Watkins, P. C., Chirgwin, J. M., Shows, T. B. Mapping FSHB, CAT, and CTSD to specific sites on 11p. (Abstract) Cytogenet. Cell Genet. 46: 678 only, 1987.
Siintola, E., Partanen, S., Stromme, P., Haapanen, A., Haltia, M., Maehlen, J., Lehesjoki, A.-E., Tyynela, J. Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129: 1438-1445, 2006. [PubMed: 16670177] [Full Text: https://doi.org/10.1093/brain/awl107]
Steinfeld, R., Reinhardt, K., Schreiber, K., Hillebrand, M., Kraetzner, R., Bruck, W., Saftig, P., Gartner, J. Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am. J. Hum. Genet. 78: 988-998, 2006. [PubMed: 16685649] [Full Text: https://doi.org/10.1086/504159]
Tyynela, J., Sohar, I., Sleat, D. E., Gin, R. M., Donnelly, R. J., Baumann, M., Haltia, M., Lobel, P. A mutation in the ovine cathepsin D gene causes a congenital lysosomal storage disease with profound neurodegeneration. EMBO J. 19: 2786-2792, 2000. [PubMed: 10856224] [Full Text: https://doi.org/10.1093/emboj/19.12.2786]
Vitner, E. B., Dekel, H., Zigdon, H., Shachar, T., Farfel-Becker, T., Eilam, R., Karlsson, S., Futerman, A. H. Altered expression and distribution of cathepsins in neuronopathic forms of Gaucher disease and in other sphingolipidoses. Hum. Molec. Genet. 19: 3583-3590, 2010. [PubMed: 20616152] [Full Text: https://doi.org/10.1093/hmg/ddq273]