HGNC Approved Gene Symbol: CTSF
Cytogenetic location: 11q13.2 Genomic coordinates (GRCh38) : 11:66,563,464-66,568,606 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.2 | Ceroid lipofuscinosis, neuronal, 13 (Kufs type) | 615362 | Autosomal recessive | 3 |
Cathepsin F (EC 3.4.22.41) is a member of the papain family of cysteine proteases. These enzymes represent a major component of the lysosomal proteolytic system. They are synthesized as inactive precursors consisting of a signal sequence, a propeptide, and a catalytically active mature region. Cathepsins are routed to the endosomal/lysosomal compartment via the mannose 6-phosphate receptor pathway. Activation of the proenzyme usually occurs following cleavage and dissociation of the N-terminal proregion, which constitutes a regulatory element of the enzyme's proteolytic activity. Peptides corresponding to the proregions of cysteine proteases are potent, selective inhibitors of the parent enzymes (review by Nagler et al., 1999).
By PCR of a human alveolar lung macrophage cDNA library using degenerate primers based on conserved regions of papain superfamily members, Wang et al. (1998) isolated a partial cathepsin F cDNA. Using several methods, they cloned additional cathepsin F cDNAs, including a skeletal muscle cDNA that they stated contains the entire coding region. Sequence analysis revealed that the 302-amino acid cathepsin F protein predicted from their skeletal muscle cDNA has a prodomain and a mature region but lacks a signal sequence. Transient expression of an epitope-tagged cathepsin F in mammalian cells revealed a vesicular distribution of the protein in the juxtanuclear region of the cells, a typical pattern for lysosomes. Based on these results, Wang et al. (1998) suggested that cathepsin F is targeted to the lysosomal compartment via a signal peptide-independent lysosomal targeting pathway. (Santamaria et al. (1999) and Nagler et al. (1999) later found that the cDNA cloned by Wang et al. (1998) is a partial cathepsin F cDNA lacking 5-prime coding sequence. They showed that cathepsin F does contain a signal peptide and suggested that cathepsin F is targeted to the lysosomal compartment by the mannose 6-phosphate receptor pathway.) The cathepsin F protein shares 42% sequence identity with cathepsin W (602364). Recombinant mature cathepsin F was highly active, with specific activities toward synthetic substrates comparable to those reported for cathepsin L (116880), which was the most catalytically active lysosomal cysteine protease known. Northern blot analysis demonstrated that the cathepsin F gene is ubiquitously expressed.
By searching an EST database for sequences with significant similarity to members of the papain family of cysteine proteases, Santamaria et al. (1999) identified several overlapping ESTs encoding cathepsin F. Using a probe derived from these ESTs, they screened a human prostate cDNA library and isolated a full-length cathepsin F cDNA. The predicted 484-amino acid protein has the same domain organization as other cysteine proteases, including a signal sequence, a propeptide, and a catalytic region. However, compared to the propeptide domains of other papain family proteases, the cathepsin F propeptide domain is unusually long, consisting of 251 residues. Cathepsin F also has all the structural motifs of cysteine proteases, including the essential cysteine residue of the active site. The authors suggested that at least 1 of the protein's 5 potential glycosylation sites is effectively glycosylated and has attached the mannose 6-phosphate marker required for lysosomal targeting. The human cathepsin F protein is 72% identical to mouse cathepsin F and 37% identical to human cathepsin L2 (603308). Northern blot analysis detected an approximately 2.1-kb cathepsin F transcript in most normal human tissues, with the highest expression in skeletal muscle and testis. This transcript was also found in several cancer cell lines. Santamaria et al. (1999) stated that the cathepsin F cDNA isolated by them is identical to the cathepsin F cDNA reported by Wang et al. (1998) in the 3-prime region but contains an extended open reading frame at the 5-prime end that encodes more than 180 amino acids, including a signal peptide.
Nagler et al. (1999) searched an EST database for novel cysteine proteases and identified a human cathepsin F EST. Using PCR, they amplified the full-length cathepsin F coding sequence from a human ovary cDNA library. Since the deduced 484-amino acid cathepsin F protein has a signal sequence and potential glycosylation sites, the authors suggested that cathepsin F is targeted to the endosomal/lysosomal compartment via the mannose 6-phosphate receptor pathway. The mature region of the cathepsin F protein is 26 to 42% identical to other mature human cathepsins, whereas its proregion is unique in both its length and sequence. The very long proregion can be divided into 3 regions: an N-terminal domain with a cystatin-like fold, an approximately 50-residue flexible linker peptide, and a C-terminal domain that is similar to the proregion of cathepsin L-like enzymes. Cathepsin F is the first cysteine protease zymogen identified that contains a cystatin-like domain. Cystatins (see 603253) are reversible tight-binding inhibitors of lysosomal cysteine proteases and are believed to regulate proteolytic activity in vivo. The cystatin-like domain of cathepsin F contains some of the elements known to be important for inhibitory activity. Nagler et al. (1999) noted that the cathepsin F cDNA reported by Wang et al. (1998) lacks the 5-prime untranslated region and 226 bp of coding sequence, including the initiating ATG codon and the nucleotides encoding the signal peptide.
By FISH and analysis of somatic cell hybrids, Santamaria et al. (1999) mapped the CTSF gene to 11q13, the same region where the cathepsin W gene is located.
In affected members of 2 unrelated families with autosomal recessive Kufs-type neuronal ceroid lipofuscinosis (CLN13; 615362), Smith et al. (2013) identified homozygous or compound heterozygous mutations in the CTSF gene (603539.0001-603539.0003). The mutations, which were found by linkage analysis combined with exome sequencing, segregated with the disorder and were not found in several large control databases. Sequencing of the CTSF gene in 22 unrelated probands with suspected Kufs disease identified compound heterozygous mutations (603539.0004-603539.0005) in 1 patient. Molecular modeling predicted that the mutations were pathogenic, and Smith et al. (2013) noted that Ctsf-null mice develop a similar neurodegenerative disorder (Tang et al., 2006). The findings implicated CTSF dysfunction in this disorder, which was characterized by adult onset of progressive cognitive decline and motor dysfunction leading to dementia and often early death.
In affected members of an Italian family with CLN13, Di Fabio et al. (2014) identified a homozygous splice site mutation in the CTSF gene (603539.0006).
Tang et al. (2006) found high expression of the Ctsf gene in murine adrenal gland, liver, kidney, testis, and ovary, with lower expression in the heart and uterus. Expression was also found in lysosomes within cells of the brain and spinal cord. Ctsf-null mice developed normally, but had onset of a progressive neurologic disorder between 12 and 16 months of age. Mutant mice showed progressive difficulty walking, with hind leg weakness, decline in motor coordination, and general wasting. Other features included tonic hind leg extension, poor balance, tremor, and spasticity. Some mice had seizures. Ctsf-null mice died within 4 to 6 months of symptom onset. Postmortem examination showed substantial gliosis in the brain and spinal cord, neuronal loss, and an accumulation of cytoplasmic eosinophilic and autofluorescent granules in neurons and glial cells. Ultrastructural analysis confirmed membrane-bound lamellar inclusions in fingerprint patterns, consistent with lipofuscin. The phenotype was reminiscent of human adult-onset neuronal ceroid lipofuscinosis (see, e.g., CLN4A, 204300), but no CTSF mutations were identified in 13 unrelated patients with that disorder.
In a French Canadian woman, born of consanguineous parents, with adult-onset neuronal ceroid lipofuscinosis-13 (CLN13; 615362), Smith et al. (2013) identified a homozygous c.962A-G transition in exon 7 of the CTSF gene, resulting in a gln321-to-arg (Q321R) substitution at a highly conserved residue in the peptidase C1 domain towards the C-terminal end. The mutation, which was found by linkage analysis combined with exome sequencing and confirmed by Sanger sequencing, was not found in several large control databases and segregated with the disorder in the family. Molecular modeling predicted that the Q321R substitution would result in a conformational change in the binding loop that would lower catalytic efficiency.
In 2 Italian sibs with adult-onset neuronal ceroid lipofuscinosis-13 (CLN13; 615362), Smith et al. (2013) identified compound heterozygous mutations in the CTSF gene: a c.1373G-C transversion in exon 12 resulting in a gly458-to-ala (G458A) substitution, and a c.1439C-T transition in exon 13 resulting in a ser480-to-leu (S480L; 603539.0003) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in several large control databases. Both mutations occurred at highly conserved residues in the peptidase C1 domain towards the C-terminal end. Molecular modeling predicted that each mutation would lead to a conformational change or protein misfolding.
For discussion of the ser480-to-leu (S480L) mutation in the CTSF gene that was found in compound heterozygous state in patients with adult-onset neuronal ceroid lipofuscinosis-13 (CLN13; 615362) by Smith et al. (2013), see 603539.0002.
In a 41-year-old Australian woman with adult-onset neuronal ceroid lipofuscinosis-13 (CLN13; 615362), Smith et al. (2013) identified compound heterozygous mutations in the CTSF gene: a c.962A-G transition in exon 5 resulting in a tyr231-to-cys (Y231C; rs143889283) substitution at a highly conserved residue in the 129 propeptide inhibitor domain, and a 1-bp deletion in exon 7 (c.954delC) resulting in a frameshift and premature termination (Ser319LeufsTer27; 603539.0005). Neither variant was present in 2 large control databases, but the Y231C substitution was found in heterozygous state in 1 (0.012%) of 4,295 Americans of European ancestry.
For discussion of the 1-bp deletion in the CTSF gene (c.954delC) that was found in compound heterozygous state in a patient with adult-onset neuronal ceroid lipofuscinosis-13 (CLN13; 615362) by Smith et al. (2013), see 603539.0004.
In 3 members of an Italian family with adult-onset neuronal ceroid lipofuscinosis-13 (CLN13; 615362), Di Fabio et al. (2014) identified a homozygous G-to-C transversion (c.213+1G-C, NM_003793.3) in intron 1 of the CTSF gene, resulting in the removal of exon 1. The mutation segregated with the disorder in the family and was not found in the dbSNP, 1000 Genomes Project, or Exome Sequencing Project databases, or in 150 ethnically matched controls. Patient-derived fibroblasts showed a stable mutant mRNA transcript lacking exon 1. The mutation was predicted to truncate the N-terminus of cathepsin F and to result in loss of function; additional functional studies were not performed.
Di Fabio, R., Moro, F., Pestillo, L., Meschini, M. C., Pezzini, F., Doccini, S., Casali, C., Pierelli, F., Simonati, A., Santorelli, F. M. Pseudo-dominant inheritance of a novel CTSF mutation associated with type B Kufs disease. Neurology 83: 1769-1770, 2014. [PubMed: 25274848] [Full Text: https://doi.org/10.1212/WNL.0000000000000953]
Nagler, D. K., Sulea, T., Menard, R. Full-length cDNA of human cathepsin F predicts the presence of a cystatin domain at the N-terminus of the cysteine protease zymogen. Biochem. Biophys. Res. Commun. 257: 313-318, 1999. [PubMed: 10198209] [Full Text: https://doi.org/10.1006/bbrc.1999.0461]
Santamaria, I., Velasco, G., Pendas, A. M., Paz, A., Lopez-Otin, C. Molecular cloning and structural and functional characterization of human cathepsin F, a new cysteine proteinase of the papain family with a long propeptide domain. J. Biol. Chem. 274: 13800-13809, 1999. [PubMed: 10318784] [Full Text: https://doi.org/10.1074/jbc.274.20.13800]
Smith, K. R., Dahl, H.-H. M., Canafoglia, L., Andermann, E., Damiano, J., Morbin, M., Bruni, A. C., Giaccone, G., Cossette, P., Saftig, P., Grotzinger, J., Schwake, M., and 11 others. Cathepsin F mutations cause type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis. Hum. Molec. Genet. 22: 1417-1423, 2013. [PubMed: 23297359] [Full Text: https://doi.org/10.1093/hmg/dds558]
Tang, C.-H., Lee, J.-W., Galvez, M. G., Robillard, L., Mole, S. E., Chapman, H. A. Murine cathepsin F deficiency causes neuronal lipofuscinosis and late-onset neurological disease. Molec. Cell. Biol. 26: 2309-2316, 2006. [PubMed: 16508006] [Full Text: https://doi.org/10.1128/MCB.26.6.2309-2316.2006]
Wang, B., Shi, G.-P., Yao, P. M., Li, Z., Chapman, H. A., Bromme, D. Human cathepsin F: molecular cloning, functional expression, tissue localization, and enzymatic characterization. J. Biol. Chem. 273: 32000-32008, 1998. [PubMed: 9822672] [Full Text: https://doi.org/10.1074/jbc.273.48.32000]