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.

OFP is a common symptom experienced by a quarter of the adult population, of whom only 46% seek treatment. The prevalence is higher in women and younger age groups.

Amelogenesis imperfecta (AI) is a group of inherited defects of dental enamel formation that shows both clinical and genetic heterogeneity. To date, mutations in the gene encoding amelogenin have been shown to underlie a subset of the X-linked recessive forms of AI. Although none of the genes underlying autosomal-dominant or autosomal-recessive AI have been identified, a locus for a local hypoplastic form has been mapped to human chromosome 4q11-q21. In the current investigation, we have analysed a family with an autosomal-dominant, smooth hypoplastic form of AI. Our results have shown that a splicing mutation in the splice donor site of intron 7 of the gene encoding the enamel-specific protein enamelin underlies the phenotype observed in this family. This is the first autosomal-dominant form of AI for which the genetic mutation has been identified. As this type of AI is clinically distinct from that localized previously to chromosome 4q11-q21, these findings highlight the need for a molecular classification of this group of disorders.

Dentine dysplasia type II is an autosomal dominant disorder in which mineralization of the dentine of the primary teeth is abnormal. On the basis of the phenotypic overlap between, and shared chromosomal location with, dentinogenesis imperfecta type II, a second disorder of dentine mineralization, it has been proposed that the two conditions are allelic. As recent studies have shown that dentinogenesis imperfecta type II results from mutation of the bicistronic dentine sialophosphoprotein gene (DSPP ), we have tested this hypothesis by sequencing DSPP in a family with a history of dentine dysplasia type II. Our results have shown that a missense change, which causes the substitution of a tyrosine for an aspartic acid in the hydrophobic signal peptide domain of the protein, underlies the phenotype in this family. Biochemical analysis has further demonstrated that this mutation causes a failure of translocation of the encoded proteins into the endoplasmic reticulum, and is therefore likely to lead to a loss of function of both dentine sialoprotein and dentine phosphoprotein.