IDENTIFYING THE PAPILLON LEFEVRE SYNDROME GENE DEFECT

识别巴比龙勒菲佛综合症基因缺陷

• 批准号: 2752252
• 负责人: Thomas C Hart
• 金额: $ 4.48万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 1999-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2752252
• 关键词: chromosomes; clinical research; diagnosis design /evaluation; family genetics; gene expression; gene mutation; genetic disorder diagnosis; genetic markers; genotype; gingiva; homozygote; human genetic material tag; human subject; keratosis; linkage mapping; nucleic acid sequence; periodontitis; polymerase chain reaction

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.

在这项研究中，我们建议确定的基因突变（S）负责Papillon Lefevre综合征（PLS）。 PLS是一种遗传性疾病，其特征是弥漫性transgradiens掌跖角化病和严重的早发性牙周炎，导致乳牙和恒牙过早脱落。 PLS的治疗，特别是牙齿部分的治疗，是困难的，并且成功率有限。PLS是遗传作为一个简单的常染色体隐性孟德尔性状。负责PLS的基因尚未确定，PLS的分子基础是未知的。 迄今为止，PLS的原因调查仅限于少数个体的病例报告。 尽管已经报道了PLS的一些免疫学异常，但缺乏标准化的方法使得难以推断各种研究的结果并应用这些信息来开发更好的治疗方法或了解导致潜在病理学的原因。 了解这种情况的生物学基础的更好策略是首先确定负责PLS的基因和相关突变。最近，PLS基因已被报道定位于染色体11 q的8-10 cM区域。 我们还独立地将PLS基因定位于染色体11 q。 我们研究了10个有PLS血缘关系的家系，利用纯合性定位技术将PLS基因亚定位于染色体11 q的4- 5cM区域。 迄今为止，我们研究的所有10个家庭似乎都有与同一区域相关的基因缺陷。 我们已经确定了10个额外的近亲家庭与PLS。 这20个PLS家庭代表了有史以来最大的PLS人口研究。 我们提出了3种广泛的策略来识别负责PLS的基因突变。 我们将继续基因定位研究，以进一步完善PLS基因（特定目标编号1）的遗传候选区域。 我们建议进行分子研究来解析候选区域的物理和遗传图谱，以帮助识别PLS位点（特定目标编号2）的候选基因和EST。 然后将使用基因鉴定和突变分析的策略来评估基因并鉴定这些家族中负责PLS的特定突变（特定目标编号3）。这些特定目的的完成将使我们能够确定负责PLS的基因，并提供重要信息以了解其生物学基础。 PLS的遗传基础的鉴定对PLS的诊断和治疗具有意义，并且可以提供对其他形式的牙周病中牙周破坏的易感性增加的见解，特别是对治疗反应较低的严重类型。