J Med Genet 38:96-101 doi:10.1136/jmg.38.2.96
  • Original article

Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefèvre syndrome patients


We describe a mutation and haplotype analysis of Papillon-Lefèvre syndrome probands that provides evidence of a founder effect for four separate cathepsin C mutations. A total of 25 different cathepsin C mutations have been reported in 32 families with Papillon-Lefèvre syndrome (PLS) and associated conditions. A characteristic of these findings is the diversity of different cathepsin C mutations that have been identified. To evaluate the generality of cathepsin C mutations, PLS probands representative of five reportedly unrelated Saudi Arabian families were evaluated by mutational and haplotype analyses. Sequence analysis identified two cathepsin C gene mutations: a novel exon 7 G300D mutation was found in the proband from one family, while probands from four families shared a common R272P mutation in exon 6. The R272P mutation has been previously reported in two other non-Saudi families. The presence of the R272P mutation in probands from these four Saudi families makes this the most frequently reported cathepsin C mutation. To distinguish between the presence of a possible founder effect or a mutational hot spot for the R272P mutation, we performed haplotype analysis using six novel DNA polymorphisms that span a 165 kb interval containing the cathepsin C gene. Results of haplotype analysis for genetic polymorphisms within and flanking the cathepsin C gene are consistent with inheritance of the R272P mutation “identical by descent” from a common ancestor in these four Saudi families. Haplotype analysis of multiple PLS probands homozygous for other cathepsin C mutations (W249X, Q286X, and T153I) also supports inheritance of each of these mutations from common ancestors. These data suggest that four of the more frequently reported cathepsin C mutations have been inherited from common ancestors and provide the first direct evidence for a founder effect for cathepsin C gene mutations in PLS. Identification of these six short tandem repeat polymorphisms that span the cathepsin C gene will permit haplotype analyses to determine other founder haplotypes of cathepsin C mutations in additional PLS families.