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

Papillon-Lefevre syndrome, or keratosis palmoplantaris with periodontopathi a (PLS, MIM 245000), is an autosomal recessive disorder that is mainly asce rtained by dentists because of the severe periodontitis that afflicts patie nts(1,2). Both the deciduous and permanent dentitions are affected, resulti ng in premature tooth loss. Palmoplantar keratosis, varying from mild psori asiform scaly skin to overt hyperkeratosis, typically develops within the f irst 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 r are individuals the periodontitis is mild and of late onset(3-6). The PLS l ocus has been mapped to chromosome 11q14-q21 (refs 7-9). Using homozygosity mapping in eight small consanguineous families, we have narrowed the candi date region to a 1.2-cM interval between D11S4082 and D11S931. The gene (CT SC) encoding the lysosomal protease cathepsin C (or dipeptidyl aminopeptida se I) lies within this interval. We defined the genomic structure of CTSC a nd 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 activ ity in PLS patients and reduced activity in obligate carriers.