Novel Mutations in the <i>Cathepsin C</i> Gene in Patients with Pre-pubertal Aggressive Periodontitis and Papillon-Lefèvre Syndrome

Noack, Barbara; Görgens, Heike; Hoffmann, T; Fanghänel, Jutta; Kocher, T.; Eickholz, Peter; Schackert, Hans K.

doi:10.1177/154405910408300503

Cited by 46 publications

(42 citation statements)

References 16 publications

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“…Principally an amino dipeptidase, CtsC cleaves two-residue units in the N terminus of polypeptide chains in a nonspecific manner (Turk et al 1998) and, unlike other cysteine Cts, exists in a tetrameric structure ) that blocks autoactivation . Although individuals with loss-of-function mutations in CtsC manifest prepubertal aggressive periodontitis (Noack et al 2004), Haim-Monk syndrome (Hart et al 2000), or Papillon-Lefevre syndrome (Frezzini et al 2004;Pham et al 2004), CtsC is also of interest due to its catalytic activation of several leukocyte-derived serine proteases, including granzymes A, B, and C; neutrophil elastase (NE); CtsG; proteinase 3; and mast cell chymase (Pham and Ley 1999;Wolters et al 2001;Adkison et al 2002;Mallen-St Clair et al 2004). CtsC expression by mast cells and neutrophils reduces survival during septic peritonitis (Mallen-St Clair et al 2004) and limits protection from experimental arthritis (Adkison et al 2002), respectively, indicating its role as a mediator of inflammation.…”

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confidence: 99%

Cathepsin C is a tissue-specific regulator of squamous carcinogenesis

et al. 2013

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Serine and cysteine cathepsin (Cts) proteases are an important class of intracellular and pericellular enzymes mediating multiple aspects of tumor development. Emblematic of these is CtsB, reported to play functionally significant roles during pancreatic islet and mammary carcinogenesis. CtsC, on the other hand, while up-regulated during pancreatic islet carcinogenesis, lacks functional significance in mediating neoplastic progression in that organ. Given that protein expression and enzymatic activity of both CtsB and CtsC are increased in numerous tumors, we sought to understand how tissue specificity might factor into their functional significance. Thus, whereas others have reported that CtsB regulates metastasis of mammary carcinomas, we found that development of squamous carcinomas occurs independently of CtsB. In contrast to these findings, our studies found no significant role for CtsC during mammary carcinogenesis but revealed squamous carcinogenesis to be functionally dependent on CtsC. In this context, dermal/stromal fibroblasts and bone marrow-derived cells expressed increased levels of enzymatically active CtsC that regulated the complexity of infiltrating immune cells in neoplastic skin, development of angiogenic vasculature, and overt squamous cell carcinoma growth. These studies highlight the important contribution of tissue/microenvironment context to solid tumor development and indicate that tissue specificity defines functional significance for these two members of the cysteine protease family.

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confidence: 99%

Cathepsin C is a tissue-specific regulator of squamous carcinogenesis

et al. 2013

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“…The p.G301S and the p.R272P mutation, which was discovered in typical PLS families [12-14, 17, 26, 44, 49, 50], have been also associated with atypical cases, late onset of periodontitis [45] and mild skin lesions [16]. A seven base-pair deletion (p.T189FS199X) in one prepubertal periodontitis family [27] was also found in two of the analyzed typical PLS families and has been reported previously in PLS [26]. These results are confirmed by a recent study that failed to associate the severity of hyperkeratosis and periodontitis with different CTSC genotypes in 39 PLS patients [51].…”

Section: Discussionmentioning

confidence: 98%

Cytokine production by leukocytes of Papillon–Lefèvre syndrome patients in whole blood cultures

et al. 2011

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Papillon-Lefèvre syndrome (PLS) is characterised by aggressively progressive periodontitis combined with palmo-plantar hyperkeratosis. It is caused by "loss of function" mutations in the cathepsin C gene. The hypothesis behind this study is that PLS patients' polymorphonuclear leukocytes (PMNs) produce more proinflammatory cytokines to compensate for their reduced capacity to neutralize leukotoxin and to eliminate Aggregatibacter actinomycetemcomitans. Production of more interleukin (IL)-8 would result in the attraction of more PMNs. The aim of this study was to evaluate the cytokine profile in PLS patients' blood cultures. Blood was sampled from eight PLS patients (one female) from six families (antiinfective therapy completed: six; edentulous: two) with confirmed cathepsin C mutations and deficient enzyme activity. Nine healthy males served as controls. Whole blood cultures were stimulated with highly pure lipopolysaccharide (LPS) from Escherichia coli R515 and IL-1β plus tumor necrosis factor (TNF)-α. Thereafter, release of IL-1β (stimulation: LPS and LPS plus adenosine triphosphate), IL-6, IL-8, interferon-inducible protein (IP)-10, and interferon (IFN)-γ (stimulation: LPS, IL-1β/TNFα) were detected by ELISA. Medians of cytokine release were, with the exception of IP-10, slightly higher for PLS than for controls' cultures. None of these differences reached statistical significance. Increased production of IL-1β, IL-6, IL-8, IP-10, or IFNγ as a significant means to compensate for diminished activity and stability of polymorphonuclear leukocyte-derived proteases could not be confirmed in this study. Cytokine profiles in blood cultures may not be used to identify PLS patients.

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“…Namely, the majority of the studies on the genetic background of PLS did not include mutational analyses of the whole 5′-UTR [10,33,36,37,38,39]. Only a limited number of studies reported analysis of the CTSC 5′-regulatory region in families from several ethnic groups; however, no mutations were discovered in the 5′-UTR [6,9,40]. Thus, to the best of our knowledge, the present work is the first report of a CTSC mutation in the 5′-UTR, presumably affecting its regulatory function.…”

Section: Discussionmentioning

confidence: 99%

Cathepsin C Gene 5′-Untranslated Region Mutation in Papillon-Lefèvre Syndrome

et al. 2012

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Background: Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar keratoderma together with a severe form of generalized aggressive periodontitis and associated with mutations in cathepsin C gene (CTSC). Objective: To investigate the clinical and mutational characteristics of 6 PLS patients from 4 unrelated Slovenian families. Methods:CTSC mutational and functional analyses were performed. Results: In all patients, a novel homozygous substitution, c.-55C>A, in the CTSC 5′-untranslated region (UTR) was detected on genomic DNA level and confirmed by mRNA analysis, resulting in the almost complete loss of CTSC mRNA expression and CTSC activity. In silico analysis revealed the potential of the mutation to disrupt putative transcription factor binding sites (TFBSs) for AP-2 and Sp families of transcription factors. Conclusion: Identification of a novel CTSC 5′-UTR mutation together with a severe reduction of CTSC mRNA expression and virtually nonexistent CTSC activity was suggestive of a novel mechanism of TFBS dysfunction associated with PLS.

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Novel Mutations in the Cathepsin C Gene in Patients with Pre-pubertal Aggressive Periodontitis and Papillon-Lefèvre Syndrome

Cited by 46 publications

References 16 publications

Cathepsin C is a tissue-specific regulator of squamous carcinogenesis

Cathepsin C is a tissue-specific regulator of squamous carcinogenesis

Cytokine production by leukocytes of Papillon–Lefèvre syndrome patients in whole blood cultures

Cathepsin C Gene 5′-Untranslated Region Mutation in Papillon-Lefèvre Syndrome

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