Alternative titles; symbols
HGNC Approved Gene Symbol: CTSC
SNOMEDCT: 40158001, 719973009;
Cytogenetic location: 11q14.2 Genomic coordinates (GRCh38): 11:88,293,592-88,337,736 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q14.2 | Haim-Munk syndrome | 245010 | Autosomal recessive | 3 |
| Papillon-Lefevre syndrome | 245000 | Autosomal recessive | 3 | |
| Periodontitis 1, juvenile | 170650 | Autosomal recessive | 3 |
Cathepsin C, or dipeptidyl aminopeptidase I (EC 3.4.14.1), is a lysosomal protease capable of removing dipeptides from the amino terminus of protein substrates. Unlike cathepsins B (116810), H(116820), L (116880), and S (116845), which are small monomeric enzymes, cathepsin C is a large (200 kD) oligomeric protein (Paris et al. (1995)).
Paris et al. (1995) cloned a human cDNA encoding cathepsin C. The gene encodes a 463-amino acid polypeptide with predicted features of the papain family of cysteine proteases. Northern blot analysis by Rao et al. (1997) showed that cathepsin C is expressed at high levels in lung, kidney, and placenta, and at moderate or low levels in a variety of other organs. Rao et al. (1997) found no classic TATA or CCAAT box in the 5-prime flanking region of the gene, but did detect several possible tissue-specific regulatory elements.
Pham et al. (1997) cloned the mouse cathepsin C gene and reported that it is 77.8% identical to the human gene at the amino acid level.
The CTSC gene was reported by Rao et al. (1997) to have 2 exons and to span approximately 3.5 kb. Because their attempts to amplify exon 1 of the CTSC gene using a variety of exonic and flanking intronic primers repeatedly failed, Toomes et al. (1999) recharacterized the genomic organization of CTSC. Sequence analysis of a CTSC-containing BAC clone revealed that the cDNA exon 1 sequence reported by Rao et al. (1997) is actually divided into 6 exons. The CTSC gene is therefore encoded by 7 exons that are separated by 6 introns, all of which fall in positions identical to those described for the mouse gene.
Hart et al. (1999) determined that the cathepsin C gene spans 4.7 kb.
Rao et al. (1997) noted that among immune cells, the CTSC message is expressed at high levels in polymorphonuclear leukocytes and alveolar macrophages and their precursors. Treatment of lymphocytes with interleukin-2 (IL2; 147680) resulted in a significant increase in CTSC mRNA levels, suggesting that this gene is subject to transcriptional regulation. However, Pham et al. (1997) reported that activation of mouse splenocytes by IL2 did not alter the level of cathepsin C mRNA or protein.
The cathepsin C protein is processed into a mature proteolytically active enzyme consisting of a heavy chain, a light chain, and a propeptide that remains associated with the active enzyme (Wolters et al., 1998; Cigic et al., 2000). Whereas the other cathepsins are monomers, cathepsin C is a 200-kD tetramer with 4 identical subunits, each composed of the 3 different polypeptide chains.
Rao et al. (1997) used fluorescence in situ hybridization to map the CTSC gene to chromosome 11q14.1-q14.3.
Papillon-Lefevre Syndrome
Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathia (PLS; 245000), is an autosomal recessive disorder that is ascertained mainly by dentists because of the severe periodontitis that afflicts patients. The PLS locus had been mapped to 11q14-q21 in a region overlapping that containing the CTSC gene. Using homozygosity mapping in 8 small consanguineous families, Toomes et al. (1999) narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. With this further evidence making CTSC a strong candidate gene, Toomes et al. (1999) defined the genomic structure of the CTSC gene and found mutations in all 8 families. In 2 of these families, they used a functional assay to demonstrate an almost total loss of the activity of this lysosomal protease in PLS patients and reduced activity in obligate carriers. Mutations identified by Toomes et al. (1999) included 1 nonsense mutation, 1 mutation of a AG acceptor splice site, and 6 missense mutations (see, e.g., 602365.0001-602365.0003, 602365.0013).
Toomes et al. (1999) selected CTSC as a candidate for further analysis, partly because other conditions with lysosomal dysfunctions such as Chediak-Higashi syndrome (214500) also feature severe early onset periodontitis. Lack of functional CTSC in PLS may be associated with a reduced host response against bacteria in dental plaque and possibly at other sites. CTSC has an essential role in the activation of granule serine proteases expressed in bone marrow-derived effector cells of both myeloid and lymphoid series. These proteases are implicated in a wide variety of immune and inflammatory processes, including phagocytic destruction of bacteria and local activation or deactivation of cytokines and other inflammatory mediators. CTSC is also required for processing and activation of the T-lymphocyte granzymes A (GZMA; 140050) and B (GZMB; 123910), the key agents of T cell-mediated cell killing. The lack of a generalized T-cell immunodeficiency in PLS suggests that other pathways can compensate for loss of cathepsin C in most tissues. The PLS phenotype also suggests a role for cathepsin C in epithelial differentiation or desquamation. Aberrant epithelial differentiation may affect the junctional epithelium that binds the gingiva to the tooth surface, possibly weakening the mechanical barrier to periodontal pathogens.
Pham et al. (2004) found that, unlike mice lacking Dppi, cytotoxic lymphocytes from humans with PLS maintained lymphocyte-activated killer cell function and significant GZMA and GZMB activity. Loss of DPPI activity was associated with a severe reduction in the activity and stability of neutrophil-derived serine proteases, but neutrophils from PLS patients did not uniformly have a defect in their ability to kill Staphylococcus aureus and Escherichia coli, suggesting that alternative mechanisms to serine proteases exist in humans for killing these bacteria. Pham et al. (2004) proposed that these observations provide a molecular explanation for the lack of a generalized T-cell immunodeficiency phenotype in patients with PLS.
Hart et al. (1999) found 4 mutations in the CTSC gene in 5 consanguineous Turkish families with PLS (602365.0004-602365.0007). One nonsense mutation in exon 1 and 3 nonsense mutations in exon 2 (2 deletions and a substitution) were found. All affected individuals were homozygous for CTSC mutations from a common ancestor. Clinical features were not seen in any of the obligate carriers. RT-PCR studies showed CTSC expression in the epithelium of the palms, soles, knees, and oral keratinized gingiva.
Hart et al. (2000) reported mutations in the CTSC gene in patients with PLS from Australia, England, Iran, Turkey, and the U.S. Mutations were identified in 14 of 20 families studied. Nine of 15 mutations identified were missense.
Using haplotype analysis of 27 individuals with PLS, Zhang et al. (2001) demonstrated that there was likely to be a founder effect for 4 previously described causative mutations in the cathepsin C gene.
Haim-Munk Syndrome
Of the many palmoplantar keratoderma conditions, only Papillon-Lefevre syndrome and Haim-Munk syndrome (HMS; 245010) are associated with premature periodontal destruction. While cases of PLS had been identified throughout the world, HMS had been described only in members of the Jewish religious isolate from Cochin, India. It had been suggested by Gorlin et al. (1976) that PLS and HMS were clinical variants. Hart et al. (2000) found a missense mutation in the CTSC gene (602365.0006) in 4 HMS sibships of the Cochin isolate. They also found a nonsense mutation at the same codon (602365.0007) in a Turkish family with PLS, confirming that PLS and HMS are allelic.
Aggressive Periodontitis 1
Hewitt et al. (2004) identified mutations in the CTSC gene (602365.0012 and 602365.0016) in only 1 of 2 families with aggressive periodontitis (170650). They suggested that the disorder is genetically heterogeneous and that one form represents a partially penetrant Papillon-Lefevre syndrome.
Pham and Ley (1999) generated mice lacking Dppi. Cytotoxic lymphocytes from these mice had normal amounts of Gzma and Gzmb, but these enzymes lacked their prodomains and were essentially inactive. Pham and Ley (1999) concluded that DPPI is required for processing of the prodomains of GZMA and GZMB and that alternative proteases cannot substitute for granzymes in cytotoxic cells.
By enzyme histochemistry and solution-based assays using mast cells from Dppi -/- mice, Wolters et al. (2001) showed that Dppi was required for processing and activation of mast cell chymases (see CMA1; 118938), but not tryptases (see TPSAB1; 191080).
Pagano et al. (2007) stated that elastase-induced abdominal aortic aneurysms in the mouse are accompanied by increased aortic wall expression of Dppi. They found that mice with a loss-of function mutation in Dppi were resistant to elastase-induced abdominal aortic aneurysms, with diminished recruitment of neutrophils to the elastase-injured aortic wall and impaired local production of Cxcl2 (139110). Pagano et al. (2007) concluded that DPPI and/or granule-associated serine proteases are necessary for neutrophil recruitment into the diseased aorta and that these proteases amplify vascular wall inflammation leading to abdominal aortic aneurysm.
In a consanguineous Papillon-Lefevre syndrome (PALS; 245000) family with affected sister and brother (their family 7), Toomes et al. (1999) found homozygosity for a nonsense mutation in the CTSC gene: 628C-T resulting in change of codon 210 in exon 4 from arginine to stop (R210X).
In their family 3 with Papillon-Lefevre syndrome (PALS; 245000), Toomes et al. (1999) identified homozygosity for a splice site mutation, a G-to-A transition at the last nucleotide of intron 3 (IVS3-1G-A).
In their family 1 with Papillon-Lefevre syndrome (PALS; 245000), Toomes et al. (1999) identified homozygosity for a 755A-T transversion in exon 5, predicted to cause a gln252-to-leu amino acid substitution.
In 2 members of a consanguineous Turkish family with Papillon-Lefevre syndrome (PALS; 245000), Hart et al. (1999) found a homozygous 856C-T transition in the CTSC gene, resulting in a glu286-to-ter (E286X) substitution.
In a consanguineous Turkish family with Papillon-Lefevre syndrome (PALS; 245000), Hart et al. (1999) found a homozygous 1-bp deletion at nucleotide 2692 (codon 349 of the CTSC gene product), causing a frameshift and premature termination 27 bases downstream.
In 4 sibships of the Cochin isolate with Haim-Munk syndrome (HMS; 245010), Hart et al. (2000) described a homozygous 2127A-G transition in the CTSC gene, causing the substitution of an arginine residue for a highly conserved glutamine residue (Q286R). The authors noted that this mutation is in the heavy chain region, the most conserved region of cathepsin C. Hart et al. (2000) also found a mutation at the same codon (Q286X; 602365.0007) in a Turkish family with Papillon-Lefevre syndrome (PALS; 245000), confirming that the 2 conditions are allelic.
In a Turkish family with Papillon-Lefevre syndrome (PALS; 245000), Hart et al. (2000) found a homozygous 2126C-T transition in the CTSC gene, resulting in a glu286-to-ter substitution (Q286X). The authors also found a missense mutation at the same codon in families from the Cochin isolate with Haim-Munk syndrome (Q286R; 602365.0006), confirming that the 2 conditions are allelic.
In their family 1 with Papillon-Lefevre syndrome (PALS; 245000), Nakano et al. (2001) identified a homozygous 116G-C transversion in the CTSC gene, resulting in a trp39-to-ser (W39S) substitution at a highly conserved residue within the cathepsin C polypeptide.
In their family 2 with Papillon-Lefevre syndrome (PALS; 245000), Nakano et al. (2001) identified a homozygous 901G-A transition in the CTSC gene, resulting in a gly301-to-ser (G301S) substitution at a highly conserved residue within the cathepsin C polypeptide. The parents were heterozygous for the mutation.
In a French family with Papillon-Lefevre syndrome (PALS; 245000), Lefevre et al. (2001) identified compound heterozygous mutations in the CTSC gene: a 1287G-C transversion in exon 7, resulting in a trp429-to-cys (W429C) substitution, and a 1-bp deletion (1056delT; 602365.0014), resulting in a frameshift and a premature stop at codon 352. W429 is thought to be critical in the active site of cysteine proteases in the light chain of cathepsin C.
In a French family with Papillon-Lefevre syndrome (PALS; 245000), Lefevre et al. (2001) identified compound heterozygous mutations in the CTSC gene: a 380A-C transversion in exon 3, resulting in a his127-to-pro (H127P) substitution, and a 96T-G transversion in exon 1, resulting in a tyr32-to-ter (W32X; 602365.0015) substitution. H127 occurs in the propeptide chain, confirming the importance of this peptide in maintaining the structural stability of the mature enzyme.
In a child (family 1) with juvenile periodontitis (170650), Hewitt et al. (2004) identified compound heterozygous mutations in the CTSC gene: a 1235A-G transition, resulting in a tyr412-to-cys (Y412C) substitution, and an 815G-A transition, resulting in an arg272-to-his (R272H; 602365.0016). The patient had negligible CTSC enzyme activity.
Aggressive Periodontitis 1
In all 4 affected members of a consanguineous Jordanian family segregating prepubertal periodontitis (170650), Hart et al. (2000) identified homozygosity for a 1040A-G transition in the CTSC gene, resulting in a tyr347-to-cys substitution (Y347C). None of those affected had palmoplantar keratoderma.
Papillon-Lefevre Syndrome
In a patient with Papillon-Lefevre syndrome (PALS; 245000), Toomes et al. (1999) had identified homozygosity for the Y347C mutation in the CTSC gene.
For discussion of the 1-bp deletion in the CTSC gene (1056delT) that was found in compound heterozygous state in a family with Papillon-Lefevre syndrome (PALS; 245000) by Lefevre et al. (2001), see 602365.0010.
For discussion of the tyr32-to-ter (Y32X) mutation in the CTSC gene that was found in compound heterozygous state in a family with Papillon-Lefevre syndrome (PALS; 245000) by Lefevre et al. (2001), see 602365.0011.
For discussion of the arg272-to-his (R272H) mutation in the CTSC gene that was found in compound heterozygous state in a child with juvenile periodontitis (170650) by Hewitt et al. (2004), see 602365.0012.
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