title: Evidence of a founder effect for four cathepsin C gene mutations in Papillon-Lefèvre syndrome patients.
abstract: 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.
authors.affiliation: Department of Oral Biology, University of Pittsburgh School of Dental Medicine, 614 Salk Hall, 3501 Terrace Street, Pittsburgh, PA 15261, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Lundgren
authors.forename: S
authors.initials: S
authors.lastname: Renvert
authors.forename: D N
authors.initials: DN
authors.lastname: Tatakis
authors.forename: E
authors.initials: E
authors.lastname: Firatli
authors.forename: C
authors.initials: C
authors.lastname: Uygur
authors.forename: P S
authors.initials: PS
authors.lastname: Hart
authors.forename: M C
authors.initials: MC
authors.lastname: Gorry
authors.forename: J J
authors.initials: JJ
authors.lastname: Marks
authors.forename: T C
authors.initials: TC
authors.lastname: Hart
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D020789:Cathepsin C / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D018703:Founder Effect; D006239:Haplotypes; D006801:Humans; D018895:Microsatellite Repeats; D009154:Mutation; D010214:Papillon-Lefevre Disease / Q000235:genetics*; D017354:Point Mutation
chemical_list: D004247:DNA; D020789:Cathepsin C