Disease relevance of CTSC

• Papillon-Lefèvre syndrome (PLS) is an autosomal recessive palmoplantar keratoderma caused by cathepsin C (CTSC) gene mutations [1].
• We have previously reported that loss-of-function mutations in the cathepsin C gene (CTSC) result in Papillon-Lefèvre syndrome, an autosomal recessive condition characterized by palmoplantar keratosis and early-onset, severe periodontitis [2].
• This was confirmed by analyses of the CTSC activity in 30 subjects with aggressive periodontitis and age-sex matched controls, which demonstrated that there was no significant difference between these two groups (1,728.7 +/- SD 576.8 micro moles/mg/min vs. 1,678.7 +/- SD 527.2 micro moles/mg/min, respectively, p = 0.73) [2].
• Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations [2].
• Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients [3].

Psychiatry related information on CTSC

• OBJECTIVE: To evaluate neurocognitive impairment in patients with persistent arthralgia, fatigue, and subjective memory loss in patients after Lyme disease (post-Lyme syndrome, PLS) [4].
• Neurobehavioral effects of prenatal alcohol: Part III. PLS analyses of neuropsychologic tests [5].
• PLS model building: a multivariate approach to personality test data [6].
• PLS algorithms have employed to model the time-response (formation and destruction of emitter).The influence of the presence of two metals and the non-linearity relationship between response and concentration have been evaluated in the signal [7].
• An ethologist aboard HMS Beagle: the young Darwin's observations on animal behavior [8].

High impact information on CTSC

• Most PLS patients display both periodontitis and hyperkeratosis [3].
• Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis [3].
• The PLS locus has been mapped to chromosome 11q14-q21 (refs 7, 8, 9) [3].
• Selective inhibition of dipeptidyl peptidase I (DPPI), a lysosomal thiol protease highly enriched in cytotoxic lymphocytes, prevented all natural killer (NK) toxic effects of such agents [9].
• However, some NK nontoxic DPPI substrates were found to be comparable with Leu-Leu-OMe in avidity for this transport process [9].

Chemical compound and disease context of CTSC

• The myeloid tumor lines U937, HL60, and THP-1 were found to be uniformly enriched in DPPI and susceptible to Leu-Leu-OMe but not Leu-OMe toxicity [10].
• These peptides were further fragmented by a variety of cleavage reagents such as cyanogen bromide, chymotrypsin, Staphylococcus aureus protease, subtilisin, and cathepsin C to isolate individual S-[14C]carboxymethylcysteine-containing peptides [11].
• Previous studies have demonstrated that the selective toxicity of leucyl-leucine methyl ester (Leu-Leu-OMe) for cytotoxic lymphocytes and myeloid cells is dependent on intracellular conversion to membranolytic metabolites by the acyl transferase activity of the granule enzyme dipeptidyl peptidase I (DPPI) that is enriched in these cells [12].
• We found the dog C2 mastocytoma cell line to be the richest source yet described for DPPI, purifying up to 200 microg of enzyme per g of cells [13].
• In this study, the pulse-amplitude-modulation (PAM)-fluorometric method was used to evaluate the difference in the sensitivity to mercury (Hg) and metolachlor of six algal species: Ankistrodesmus falcatus, Selenastrum capricornutum, Chlorella vulgaris, Nannoplankton (PLS), Microcystis aeruginosa and Pediastrum biwae [14].

Biological context of CTSC

• The 4.7 kb CTSC gene consists of two exons [15].
• The affected individuals in the other prepubertal periodontitis family not only lacked CTSC mutations, but in addition did not share the haplotypes at the CTSC locus [2].
• Our data also suggest that a complete loss-of-function appears to be necessary for the manifestation of the phenotype, making it unlikely that weak CTSC mutations are a cause of aggressive periodontitis [2].
• The disease is caused by mutations in the cathepsin C gene (CTSC) that maps to chromosome 11q14 [16].
• The results suggest that cathepsin L could be an important activator of DPPI in vivo and that cathepsin D and possibly the cystatins may contribute to DPPI downregulation [17].

Anatomical context of CTSC

• By RT-PCR, we found CTSC is also expressed in epithelial regions commonly affected by PLS, including the palms, soles, knees, and oral keratinised gingiva [15].
• The CTSC message is expressed at high levels in a variety of immune cells including polymorphonuclear leucocytes, macrophages, and their precursors [15].
• Biochemical analysis demonstrated almost no detectable CTSC activity in leukocytes of all three probands [16].
• Biochemical analysis was performed for CTSC, cathepsin G (CTSG), and elastase activity in neutrophils for all members of the nuclear family [18].
• DPPI content was found to be highest among cytotoxic lymphocytes and myeloid cells [19].

Associations of CTSC with chemical compounds

• Sequence analysis of CTSC in the proband revealed a homozygous mutation at codon 196 (587T-->C) within exon 4 that altered the conserved leucine to proline (Leu196Pro), whereas the patient's mother was heterozygous for that mutation [20].
• Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases [21].
• Human cathepsin C thus appears to differ qualitatively from other cysteine proteinases of different origin [22].
• Sequence analysis of the cathepsin C gene from PPP affected subjects from this Jordanian family indicated that all were homozygous for a missense mutation (1040A-->G) that changes a tyrosine to a cysteine [23].
• In Group I only heparin was given according to the results of the Hepcon HMS Plus. In Group II aprotinin was added with a bolus of 1 x 10(6) kallikrein inhibiting units (KIU) for the patient immediately before initiation of CPB, 1 x 10(6) KIU in the priming solution of the CPB, and a continuous infusion of 250,000 KIU/h during CPB [24].
• Using novel reversible peptide nitrile inhibitors of cathepsin C, and cell-based assays with U937 and EcoM-G cells, we determined the effects of pharmacological inhibition of cathepsin C on serine protease activity [25].

Regulatory relationships of CTSC

• The results reported in this paper should be useful in the design of better DPPI inhibitors to block granzyme maturation and granzyme-dependent apoptosis [26].

Other interactions of CTSC

• The enzymes, except cathepsin C, are endopeptidases (reviewed in Kirschke et al., 1995), although cathepsin B was found also to be a dipeptidyl carboxypeptidase (Aronson and Barrett, 1978) and cathepsin H also an aminopeptidase (Koga et al., 1992) [27].
• Introduction of the nonphysiological homophenylalanine (Hph) residue at P1 resulted in the best substrate Ala-Hph-AMC for DPPI (k(cat)/K(m)=9,000,000M(-1)s(-1)) [26].
• In the homozygous state, this mutation was associated with an almost complete loss of activity of CTSC, CTSG, and elastase [18].
• Independent mutations (c.318-1G-->A and c.817G-->C/p.W272C) were identified in CTSC and TYR, respectively, that were shared by the affected individuals in both families [28].
• Purified DPPI exhibited both hydrolytic and transpeptidase (polymerase) activity [19].

Analytical, diagnostic and therapeutic context of CTSC

• Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations [15].
• All exons of the CTSC gene were amplified by polymerase chain reaction (PCR) using specific primers [29].
• We also tested PCA and ICA using PLS in a simulated event-related fMRI data to show their similar detection [30].
• Reduced oxygen needs for 24 hours after treatment were found for CLSE and Curosurf (porcine-derived lung surfactant, PLS) when each was compared with beractant [31].
• Two studies investigated the reliability and validity of measures of sleep and apnea using the home sleep monitoring system (HMS), which requires no instrumentation of the subject [32].

References