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Novel Mutations in the Cathepsin C Gene in Patients with Pre-pubertal Aggressive Periodontitis and Papillon-Lefèvre Syndrome
1 Department of Conservative Dentistry and Correspondence: * corresponding author, Barbara.Noack{at}mailbox.tu-dresden.de ABSTRACT Aggressive periodontitis (AP) in pre-pubertal children is often associated with genetic disorders like Papillon-Lefèvre syndrome (PLS). PLS is caused by mutations in the cathepsin C (CTSC) gene. We report a novel CTSC mutation (c.566-572del) in an otherwise healthy AP child and two novel compound heterozygous mutations (c.947T>G, c.1268G>C) in a PLS patient. We conclude that at least a subset of pre-pubertal AP is due to CTSC mutations and therefore may be an allelic variant of PLS.
Key Words: aggressive periodontitis • Papillon-Lefèvre syndrome • cathepsin C mutation TO THE EDITOR: Aggressive periodontitis (AP) affecting pre-pubertal children (PAP) is a rare form of periodontitis resulting in premature tooth loss of primary and/or permanent dentitions. In most cases, PAP is a manifestation of systemic conditions including genetic disorders such as Papillon-Lefèvre syndrome (PLS, MIM no. 245000), classified as a palmoplantar hyperkeratosis combined with severe periodontitis. PLS is caused by mutations in the cathepsin C (CTSC) gene (Toomes et al., 1999). In rare cases, PAP is an isolated finding in apparently otherwise healthy patients. A genetic causation of this periodontitis form is still under discussion (Hodge and Michalowicz, 2001). It is likely that most of these children have an unknown systemic disease that increases their susceptibility to bacterial infections. Such patients are now properly diagnosed as "Periodontitis Associated with Systemic Disease" (Armitage, 2002). To date, more than 40 mutations in the CTSC gene (MIM no. 602365) have been identified worldwide in PLS and related conditions (summarized in Selvaraju et al., 2003). CTSC is a lysosomal protease that plays an essential role in immune and inflammatory processes (Pham and Ley, 1999). Most mutations have been shown to result in a loss of enzyme function (Toomes et al., 1999; PS Hart et al., 2000, 2002; Zhang et al., 2002). We performed mutation analysis in a consanguineous German family in which one relative is suffering from PAP but shows no signs of dermatological findings. The parents and the patient’s two-year-older sister had been available for examination. In the otherwise healthy 15-year-old female PAP patient, the periodontitis resulted in pre-pubertal premature tooth loss in both the primary and secondary dentitions. She did not show any findings of systemic diseases such as palmoplantar hyperkeratosis or defects in leukocyte function. No signs of AP or hyperkeratosis could be detected in the other family members. Furthermore, we examined a German non-consanguineous PLS family. Periodontal status of the PLS patient and his unaffected mother has been reported previously (Eickholz et al., 2001). The patient’s father was not available for examination. However, he was known to have no skin or periodontal findings similar to those of the child. Each subject received clinical and genetic counseling, and all subjects gave informed consent to the study protocol approved by the ethics committee of the University of Technology Dresden (reference no. EK 151102000). All subjects, including 110 unaffected controls with no evidence of PLS or aggressive periodontitis of primary dentition (60 adult aggressive periodontitis and 50 chronic periodontitis or periodontal healthy controls), received periodontal examinations, and peripheral blood was obtained. The mother of the PAP child died of colon cancer in 1999. Only a periodontal status report was available. Thus, paraffin-embedded tumor tissue was used for DNA extraction after written informed consent was obtained from the husband. After DNA purification (DNA purification kit, Qiagen, Hilden, Germany), exons 2–6 of the CTSC gene, including exon/intron boundary regions, were amplified by PCR with primer pairs as previously described (Toomes et al., 1999). Exon 1 was amplified with 5'-GGCGCCCAACCCCCAATC-3' as the forward primer and 5'-AGAAAGGACGACCC GGAGGACT-3' as the reverse primer. Exon 7 was amplified in two parts with the primers 7/1F 5'-TCAGGGGTAACATGCAAAGAATA-3' and the primers 7/1R, 7/2F, and 7/2R published elsewhere (Toomes et al., 1999). Purified PCR products were directly sequenced according to the dideoxy chain-terminator method of Sanger and with the use of Automated Laser Fluorescence (A.L.F.expressTM) sequencing devices (Amersham Pharmacia Biotech, Freiburg, Germany). Generated sequences (ALFwin Sequence Analyser 2.00 software, Amersham Pharmacia Biotech, Freiburg, Germany) were aligned with published CTSC sequences (GenBank accession no. NT_008984). We confirmed DNA sequence variants by sequencing at least two independent PCR products.
Sequence analysis of the CTSC gene identified three novel mutations. The affected German Caucasian PAP patient carried a homozygous deletion of 7 nucleotides in exon 4 (c.566_572del), creating a premature stop codon 11 amino acids downstream (Fig.
Here we describe the first compound heterozygous mutations in the CTSC gene in a German family and the fifth compound heterozygous mutation worldwide in this gene in PLS patients (PS Hart et al., 2000; Allende et al., 2001; Zhang et al., 2002). It has been demonstrated that CTSC gene mutations altering evolutionarily conserved amino acids are associated with almost complete absence of CTSC activity and with the PLS phenotype when both alleles are affected (Zhang et al., 2002). The compound heterozygous gene mutations described herein alter highly evolutionarily conserved amino acids and are located in the functional domain of the protein (Turk et al., 2001). In addition, we report a novel homozygous c.566_572del mutation resulting in protein truncation. This is the second mutation worldwide (TC Hart et al., 2000) and the first mutation in a German patient suffering from PAP with no clinical findings other than the generalized aggressive periodontitis of the primary and secondary dentitions. Variable expressions of the phenotype in PLS have been reported in affected families (Soskolne et al., 1996; Nakano et al., 2001). Our findings confirm the hypothesis that the isolated form of pre-pubertal aggressive periodontitis can be an allelic variant of PLS with no dermatological effects but with periodontal effects, which has been proposed by TC Hart et al.(2000). Furthermore, we did not find this mutation in 110 controls, which included 60 adult aggressive periodontitis patients. Notably, a decreased CTSC activity has been demonstrated in chronic periodontitis patients not suffering from any syndrome (Soell et al., 2002). An altered CTSC function has been suggested to impair the host response to plaque bacteria (Nakano et al., 2001). Thus, the pathogenetic role of CTSC gene variants in periodontitis forms other than syndrome-associated periodontitis, as well as the function of Cathepsin C in periodontitis, could in general be considered but still remains to be confirmed.
ACKNOWLEDGMENTS This study was supported by the MedDrive program 2002 of the Dresden University of Technology. Received for publication August 8, 2003. Revision received February 9, 2004. Accepted for publication March 18, 2004. REFERENCES
Journal of Dental Research, Vol. 83, No. 5,
368-370 (2004)
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