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Identification of cathepsin C mutations in ethnically diverse papillon-Lefevre syndrome patients.

ABSTRACT: Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar keratoderma and severe, early onset periodontitis, which results from deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene. To date, 13 different cathepsin C mutations have been reported in PLS patients, all of which are homozygous for a given mutation, reflecting consanguinity.To evaluate the generality of cathepsin C mutations in PLS, we studied an ethnically diverse group of 20 unrelated families.Mutations were identified by direct automated sequencing of genomic DNA amplified for exonic regions and associated splice site junctions of the cathepsin C gene. Long range PCR was performed to determine the genomic structure of the cathepsin C gene.The cathepsin C gene spans over 46 kb, with six introns ranging in size from 1.6 to 22.4 kb. Eleven novel mutations and four previously reported mutations were identified in affected subjects from 14 families. Missense mutations were most common (9/15), followed by nonsense mutations (3/15), insertions (2/15), and deletions (1/15). Among these 14 probands, two were compound heterozygotes. Affected subjects with transgressions of the dermal lesions onto the knees or elbows or both had mutations in both the pro- and mature regions of the enzyme, although most were in the mature region.Mutations in the mature region of cathepsin C were more likely to be associated with the transgressions of the dermatological lesions, although the results were not statistically significant. A comprehensive list of all cathepsin C mutations described to date, representing 25 mutations from 32 families with PLS and related conditions, is also presented.

SUBMITTER: Hart PS

PROVIDER: S-EPMC1734492 | biostudies-other | 2000 Dec

REPOSITORIES: biostudies-other

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Identification of cathepsin C mutations in ethnically diverse papillon-Lefèvre syndrome patients.

Hart P S PS Zhang Y Y Firatli E E Uygur C C Lotfazar M M Michalec M D MD Marks J J JJ Lu X X Coates B J BJ Seow W K WK Marshall R R Williams D D Reed J B JB Wright J T JT Hart T C TC

Journal of medical genetics 20001201 12

<h4>Introduction</h4>Papillon-Lefèvre syndrome (PLS) is an autosomal recessive disorder characterised by palmoplantar keratoderma and severe, early onset periodontitis, which results from deficiency of cathepsin C activity secondary to mutations in the cathepsin C gene. To date, 13 different cathepsin C mutations have been reported in PLS patients, all of which are homozygous for a given mutation, reflecting consanguinity.<h4>Aim</h4>To evaluate the generality of cathepsin C mutations in PLS, we ...[more]

PMID: 11106356

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Project description: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.

Project description:BackgroundFew studies have evaluated the association between patient decision involvement and surgery received among racially and ethnically diverse patients or patients' attitudes about surgery and the role of family and friends in surgical treatment choices.MethodsWomen diagnosed with nonmetastatic breast cancer from June 2005 through February 2007 and reported to the Los Angeles or Detroit Surveillance, Epidemiology, and End Results registries were mailed a survey after diagnosis (N = 3133). Latina and African American women were oversampled. The response rate was 72.4%. The analytic sample (N = 1651) excluded those with stage IIIA or higher disease, self-reported clinical contraindications to breast-conserving surgery with radiation, and unclear race or ethnicity. The dependent variable was receipt of mastectomy initially. The primary independent variables were patient involvement in decision making, race or ethnicity, attitudes about recurrence, the effects of radiation, the impact of surgery on body image, and the role of others in decision making. Latinas were categorized as low or high acculturated. The association between patient involvement in decision making and the receipt of mastectomy was evaluated using logistic regression while controlling for other independent variables. All statistical tests were two-sided.ResultsThe analytic sample was 23.9% Latina (12.0% low acculturated, 11.9% high acculturated), 27.1% African American, and 48.9% white, and 17.2% received a mastectomy initially. For each racial or ethnic group, more women who reported a patient-based decision received mastectomy than those who reported a shared or surgeon-based decision (P = .022 for low-acculturated Latinas, P < .001 for other groups). Women who reported that concerns about recurrence or radiation effects were very important in their surgery decision were more likely to receive mastectomy than those less concerned (for recurrence concerns, estimated relative risk [RR] = 1.66, 95% confidence interval [CI] = 1.28 to 2.10; for radiation concerns, estimated RR = 2.35, 95% CI = 1.88 to 2.85). Women who reported that body image concerns and their spouse's opinion were very important in their surgery decision less often received mastectomy than those less concerned about body image or who placed less weight on their spouse's opinion (for body image concerns, estimated RR = 0.47, 95% CI = 0.30 to 0.74; for spouse's opinion, estimated RR = 0.53, 95% CI = 0.36 to 0.78).ConclusionGreater patient involvement in decision making was associated with receipt of mastectomy for all racial and ethnic groups. Patient attitudes about surgery and the opinions of family and friends contribute to surgical choices made by women with breast cancer.

Dataset Information

Identification of cathepsin C mutations in ethnically diverse papillon-Lefevre syndrome patients.

Publications

Identification of cathepsin C mutations in ethnically diverse papillon-Lefèvre syndrome patients.

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