Say ‘cheese’ to cathepsin C

Abstract

Why are some individuals predisposed to dental caries whereas others, despite poor dental hygiene, have strong, healthy and good-looking teeth? The answer intuitively must include a genetic predisposition in addition to specific interactions with the environment.Toomes et al.1xLoss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar hyperkeratosis. Toomes, C. et al. Nat. Genet. 1999; 23: 421–424Crossref | PubMed | Scopus (300)See all References1 have started to unravel the genetic part of the puzzle by studying families with Papillon–Lefevre syndrome – a syndrome characterized by severe periodontitis (inflammation of the fibrous tissue that surrounds and supports the root of a tooth – the periodontal membrane) and palmoplantar hyperkeratosis (a thickening of the stratum corneum of the palm and sole). The eight families they studied with the syndrome were of Egyptian, Indian/Pakistani or Lebanese origin and, in six families, consanguinity was evident, influencing the methods they used to find the gene for this autosomal recessive disorder.Using homozygosity mapping, the gene’s location was narrowed down to a small, 1.2 cM interval on chromosome 11q14–q21, the researchers then used database searches to identify genes in the region. One of the genes identified was cathepsin C (CTSC), which encodes a lysosomal protease enzyme capable of degrading certain proteins and activating others by cleaving pro-enzymes.CTSC might not be an obvious candidate because it is widely expressed; it seems that only the periodontal surface and the skin of the palms, soles, knees and elbows are affected in Papillon–Lefevre syndrome. However, as CTSC is expressed at high levels in various epithelial cells and other cells involved with the immune response, and as affected individuals are particularly susceptible to invading bacteria that challenge the gums, the protease was investigated further.Homozygous mutations were found in each of the eight families investigated, and included nonsense and frame-shift mutations as well as substitution mutations in highly conserved regions of the protein. Functional assays were carried out in individuals from two of the families, and these showed almost complete loss of CTSC activity. Reduced CTSC activity was measured in heterozygotes.The proposed rationale for the involvement of CTSC is that it activates or degrades a substrate that is important in epithelial differentiation; thus, it affects junctional epithelia at the tooth surface and in palmoplantar skin. Presumably, alternative enzymes or mechanisms can cleave the other CTSC substrates. The future management of dental health might therefore be improved by taking into account the genetic and molecular mechanisms that predispose individuals to dental decay.