Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome

Papillon-Lefevre syndrome (PLS) is an autosomal recessive disorder characte rised by palmoplantar hyperkeratosis and severe early onset periodontitis t hat results in the premature loss of the primary and secondary dentitions. A major gene locus for PLS has been mapped to a 2.8 cM interval on chromoso me 11q14. Correlation of physical and genetic maps of this interval indicat e it includes at least 40 ESTs and six known genes including the lysosomal protease cathepsin C gene (CTSC). The CTSC message is expressed at high lev els in a variety of immune cells including polymorphonuclear leucocytes, ma crophages, and their precursors. By RT-PCR, we found CTSC is also expressed in epithelial regions commonly affected by PLS, including the palms, soles , knees, and oral keratinised gingiva. The 4.7 kb CTSC gene consists of two exons. Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations. An ex on 1 nonsense mutation (856C-->T) introduces a premature stop codon at amin o acid 286. Three exon 2 mutations were identified, including a single nucl eotide deletion (2692delA) of codon 349 introducing a frameshift and premat ure termination codon, a 2 bp deletion (2673-2674delCT) that results in int roduction of a stop codon at amino acid 343, and a G-->A substitution in co don 429 (2931G-->A) introducing a premature termination codon. All PLS pati ents were homozygous for cathepsin C mutations inherited from a common ance stor. Parents and sibs heterozygous for cathepsin C mutations do not show e ither the palmoplantar hyperkeratosis or severe early onset periodontitis c haracteristic of PLS. A more complete understanding of the functional physi ology of cathepsin C carries significant implications for understanding nor mal and abnormal skin development and periodontal disease susceptibility.