The role of cathepsin C in Papillon‐Lefèvre syndrome, prepubertal periodontitis, and aggressive periodontitis

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. Hum Mutat 23:222–228, 2004. © 2004 Wiley‐Liss, Inc.

[1]  T. Hart,et al.  Identification of cathepsin C mutations in ethnically diverse Papillon-Lefèvre syndrome patients , 2000, Journal of medical genetics.

[2]  D. Brunoni,et al.  Identification of a novel cathepsin C mutation (p.W185X) in a Brazilian kindred with Papillon-Lefèvre syndrome. , 2002, Molecular genetics and metabolism.

[3]  P. Lipsky,et al.  Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I. , 1993, The Journal of biological chemistry.

[4]  T. Ley,et al.  Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J. Uitto,et al.  Papillon-Lefèvre syndrome: mutations and polymorphisms in the cathepsin C gene. , 2001, The Journal of investigative dermatology.

[6]  D Lamba,et al.  Structure of human dipeptidyl peptidase I (cathepsin C): exclusion domain added to an endopeptidase framework creates the machine for activation of granular serine proteases , 2001, The EMBO journal.

[7]  R. Pain,et al.  The residual pro-part of cathepsin C fulfills the criteria required for an intramolecular chaperone in folding and stabilizing the human proenzyme. , 2000, Biochemistry.

[8]  Alan J. Barrett,et al.  [41] Cathepsin B, cathepsin H, and cathepsin L , 1981 .

[9]  D. Bowden,et al.  Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome , 1999, Journal of medical genetics.

[10]  T. Hart,et al.  Biochemical and mutational analyses of the cathepsin c gene (CTSC) in three North American families with Papillon Lefèvre syndrome , 2002, Human mutation.

[11]  T C Hart,et al.  Localisation of a gene for prepubertal periodontitis to chromosome 11q14 and identification of a cathepsin C gene mutation , 2000, Journal of medical genetics.

[12]  R. Gomez,et al.  A Novel Mutation of the Cathepsin C Gene in Papillon-Lefévre Syndrome. , 2002, Journal of periodontology.

[13]  J. Prud'homme,et al.  Novel point mutations, deletions, and polymorphisms in the cathepsin C gene in nine families from Europe and North Africa with Papillon-Lefèvre syndrome. , 2001, The Journal of investigative dermatology.

[14]  Emma Roberts,et al.  Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis , 1999, Nature Genetics.

[15]  M. Gorry,et al.  Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefèvre syndrome patients , 2001, Journal of medical genetics.

[16]  Demonstration of altered splicing with the IVS3-1G --> a mutation of cathepsin C. , 2002, Molecular genetics and metabolism.