title: 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 patients. 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 onset. 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.
authors.affiliation: Department of Medical Genetics, St. Mary's Hospital, Manchester, UK.
authors.forename: C
authors.initials: C
authors.lastname: Toomes
authors.forename: J
authors.initials: J
authors.lastname: James
authors.forename: A J
authors.initials: AJ
authors.lastname: Wood
authors.forename: C L
authors.initials: CL
authors.lastname: Wu
authors.forename: D
authors.initials: D
authors.lastname: McCormick
authors.forename: N
authors.initials: N
authors.lastname: Lench
authors.forename: C
authors.initials: C
authors.lastname: Hewitt
authors.forename: L
authors.initials: L
authors.lastname: Moynihan
authors.forename: E
authors.initials: E
authors.lastname: Roberts
authors.forename: C G
authors.initials: CG
authors.lastname: Woods
authors.forename: A
authors.initials: A
authors.lastname: Markham
authors.forename: M
authors.initials: M
authors.lastname: Wong
authors.forename: R
authors.initials: R
authors.lastname: Widmer
authors.forename: K A
authors.initials: KA
authors.lastname: Ghaffar
authors.forename: M
authors.initials: M
authors.lastname: Pemberton
authors.forename: I R
authors.initials: IR
authors.lastname: Hussein
authors.forename: S A
authors.initials: SA
authors.lastname: Temtamy
authors.forename: R
authors.initials: R
authors.lastname: Davies
authors.forename: A P
authors.initials: AP
authors.lastname: Read
authors.forename: P
authors.initials: P
authors.lastname: Sloan
authors.forename: M J
authors.initials: MJ
authors.lastname: Dixon
authors.forename: N S
authors.initials: NS
authors.lastname: Thakker
mesh_terms: D010520:Aggressive Periodontitis / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D020789:Cathepsin C / Q000172:deficiency* / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D005091:Exons; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006801:Humans; D007438:Introns; D008297:Male; D018895:Microsatellite Repeats; D010214:Papillon-Lefevre Disease / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D017354:Point Mutation
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; D020789:Cathepsin C