In this study we propose to identify the genetic mutation(s) responsible for Papillon Lefevre syndrome (PLS). PLS is a hereditary condition characterized by diffuse transgradiens palmoplantar keratosis and severe, early onset periodontitis resulting in premature loss of both the deciduous and permanent teeth. Treatment of PLS, particularly of the dental component, is difficult and of limited success. PLS is inherited as a simple autosomal recessive Mendelian trait. The gene responsible for PLS has not been identified, and the molecular basis for PLS is unknown. To date investigations of the cause of PLS have been limited to case reports of small numbers of individuals. Although a number of immunological anomalies have been reported for PLS, the lack of standardized approaches makes it difficult to extrapolate results of various studies and apply this information to develop better treatments or to understand what is causing the underlying pathology. A better strategy to understand the biologic basis of the condition is to first identify the gene and associated mutation(s) responsible for PLS. Recently, a PLS gene has been reported to be localized to an 8-10 cM region of chromosome 11q. We have also, independently localized the gene for PLS to chromosome 11q. We have studied 10 consanguineous families with PLS using homozygosity mapping to sublocalize a PLS gene to a 4-5 cM region of chromosome 11q. All 10 families we have studied to date appear to have a gene defect linked to the same region. We have identified 10 additional consanguineous families with PLS. These 20 PLS families represent the largest PLS population ever studied. We propose 3 broad strategies to identify the gene mutation(s) responsible for PLS. We will continue gene mapping studies to further refine the genetic candidate region for the PLS gene(s) (Specific Aim number 1). We propose molecular studies to resolve physical and genetic maps of the candidate region to help identify candidate genes and ESTs for the PLS locus (Specific Aim number 2). Strategies for gene identification and mutational analysis will then be used to evaluate genes and identify the specific mutation(s) responsible for PLS in these families (Specific Aim number 3). Completion of these Specific Aims should allow us to identify the gene responsible for PLS, and provide important information to understand its biologic basis. Identification of the genetic basis of PLS has implications for diagnosis and treatment of PLS and may provide insight into the increased susceptibility to periodontal destruction in other forms of periodontal diseases, particularly severe types that are less responsive to treatment.
Showing the most recent 10 out of 11 publications
