The Role of Cathepsin C in Papillon-Lefèvre Syndrome, Prepubertal Periodontitis, and Aggressive Periodontitis

Chelsee Hewitt, Derek McCormick, Gerry Linden, Dusan Turk, Igor Stern, Ian Wallace, Louise Southern, Liqun Zhang, Rebecca Howard, Pedro Bullon, Melanie Wong, Richard Widmer, Khaled Abdul Gaffar, Lama Awawdeh, Jim Briggs, Reza Yaghmai, Ethlin W. Jabs, Peter Hoeger, Oliver Bleck, Stefan G. RüdigerGregor Petersilka, Maurizio Battino, Peter Brett, Faiez Hattab, Mohamed Al-Hamed, Philip Sloan, Carmel Toomes, Mike Dixon, Jacqueline James, Andrew P. Read, Nalin Thakker

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


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. Others have also reported CTSC mutations in patients with severe prepubertal periodontitis, but without any skin manifestations. The possible role of CTSC variants in more common types of non-mendelian, early-onset, severe periodontitis ("aggressive periodontitis") has not been investigated. In this study, we have investigated the role of CTSC in all three conditions. We demonstrate that PLS is genetically homogeneous and the mutation spectrum that includes three novel mutations (c.386T > A/p. V129E, c.935A > G/p.Q312R, and c.1235A > G/p.Y412C) in 21 PLS families (including eight from our previous study) provides an insight into structure-function relationships of CTSC. 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. 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 μ moles/mg/min vs. 1,678.7 ± SD 527.2 μ moles/mg/min, respectively, p = 0.73). CTSC mutations were detected in only one of two families with prepubertal periodontitis; these did not form a separate functional class with respect to those observed in classical PLS. 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. These data suggest that prepubertal periodontitis is a genetically heterogeneous disease that, in some families, just represents a partially penetrant PLS.

Original languageEnglish (US)
Pages (from-to)222-228
Number of pages7
JournalHuman Mutation
Issue number3
StatePublished - 2004


  • Cathepsin C
  • CTSC
  • Papillon-Lefèvre syndrome
  • Periodontitis
  • PLS

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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