Identification of cathepsin C mutations in ethnically diverse Papillon-Lefevre syndrome patients

Introduction-Papillon-Lefevre syndrome (PLS) is an autosomal recessive diso rder characterised by palmoplantar keratoderma and severe, early onset peri odontitis, which results fi om deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene. To date, 13 different cathepsin C mu tations have been reported in PLS patients, all of which are homozygous for a given mutation, reflecting consanguinity. Aim-To evaluate the generality of cathepsin C mutations in PLS, we studied an ethnically diverse group of 20 unrelated families. Methods-Mutations were identified by direct automated sequencing of genomic DNA amplified for exonic regions and associated splice site junctions of t he cathepsin C gene. Long range PCR was performed to determine the genomic structure of the cathepsin C gene. Results-The cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously report ed mutations were identified in affected subjects from 14 families, Missens e mutations were most common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were compound heterozygotes. Affected subjects with transgressions of the derma l lesions onto the knees or elbows or both had mutations in both the pro- a nd mature regions of the enzyme, although most were in the mature region. Conclusion-Mutations in the mature region of cathepsin C were more likely t o be associated with the transgressions of the dermatological lesions, alth ough the results were not statistically significant. A comprehensive list o f all cathepsin C mutations described to date, representing 25 mutations fr om 32 families with PLS and related conditions, is also presented.