Mutations of the cathepsin C gene are responsible for Papillon-Lefèvre syndrome
- Thomas C Harta,
- P Suzanne Harta,
- Donald W Bowdenb,
- Michael D Michaleca,
- Scott A Callisona,
- Steve J Walkera,
- Yingze Zhangc,
- Erhan Firatlid
- aDepartment of Pediatrics, Section of Medical Genetics, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA, bDepartment of Biochemistry, Wake Forest University School of Medicine, Winston Salem, North Carolina, USA, cDepartment of Oral Medicine/Pathology, University of Pittsburgh, Pittsburgh, PA, USA, dDepartment of Periodontology, University of Istanbul School of Dentistry, Istanbul, Turkey
- Dr T C Hart, Division of Oral Biology, University of Pittsburgh, 3501 Terrace Street, 618 Salk Hall, Pittsburgh, PA 15261, USA
- Revised 23 October 1999
- Accepted 26 October 1999
Abstract
Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar hyperkeratosis and severe early onset periodontitis that 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 chromosome 11q14. Correlation of physical and genetic maps of this interval indicate it includes at least 40 ESTs and six known genes including the lysosomal protease cathepsin C gene (CTSC). The CTSCmessage is expressed at high levels in a variety of immune cells including polymorphonuclear leucocytes, macrophages, 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 kbCTSC gene consists of two exons. Sequence analysis of CTSC from subjects affected with PLS from five consanguineous Turkish families identified four different mutations. An exon 1 nonsense mutation (856C→T) introduces a premature stop codon at amino acid 286. Three exon 2 mutations were identified, including a single nucleotide deletion (2692delA) of codon 349 introducing a frameshift and premature termination codon, a 2 bp deletion (2673-2674delCT) that results in introduction of a stop codon at amino acid 343, and a G→A substitution in codon 429 (2931G→A) introducing a premature termination codon. All PLS patients were homozygous for cathepsin C mutations inherited from a common ancestor. Parents and sibs heterozygous for cathepsin C mutations do not show either the palmoplantar hyperkeratosis or severe early onset periodontitis characteristic of PLS. A more complete understanding of the functional physiology of cathepsin C carries significant implications for understanding normal and abnormal skin development and periodontal disease susceptibility.
