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Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis

Abstract

Papillon-Lefèvre syndrome, or keratosis palmoplantaris with periodontopathia (PLS, MIM 245000), is an autosomal recessive disorder that is mainly ascertained by dentists because of the severe periodontitis that afflicts patients1,2. Both the deciduous and permanent dentitions are affected, resulting in premature tooth loss. Palmoplantar keratosis, varying from mild psoriasiform scaly skin to overt hyperkeratosis, typically develops within the first three years of life. Keratosis also affects other sites such as elbows and knees. Most PLS patients display both periodontitis and hyperkeratosis. Some patients have only palmoplantar keratosis or periodontitis, and in rare individuals the periodontitis is mild and of late onset3,4,5,6. The PLS locus has been mapped to chromosome 11q14–q21 (refs 7, 8, 9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candidate region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CTSC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptidase I) lies within this interval. We defined the genomic structure of CTSC and found mutations in all eight families. In two of these families we used a functional assay to demonstrate an almost total loss of cathepsin C activity in PLS patients and reduced activity in obligate carriers.

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Figure 1: Clinical features of PLS.
Figure 2: Fine-mapping of the PLS locus.
Figure 3: Segregation of CTSC mutations in PLS families 6 and 7.
Figure 4: Reduction of cathepsin C activity in PLS.

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Acknowledgements

We thank the patients and their families for help with this study, and A. Naylor, A. Wallace, A. Carradice, G. Karbani and A. Jackson for contribution to this work. This study was funded in part by the MRC, Wellcome Trust (grant 058423) and Northern and Yorkshire Regional Health Authority.

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Correspondence to Nalin S. Thakker.

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Toomes, C., James, J., Wood, A. et al. Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 23, 421–424 (1999). https://doi.org/10.1038/70525

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