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: 6164427
• 负责人: Thomas C Hart
• 金额: $ 18.74万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 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 2002-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6164427
• 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，我们提出确定基因突变(s)负责Papillon Lefevre综合征（PLS）。PLS是一种遗传性疾病，其特征是弥漫性跨梯度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，是困难和有限的成功。PLS作为一种简单的常染色体隐性孟德尔性状遗传。负责PLS的基因尚未确定，PLS的分子基础是未知的。迄今为止，对PLS病因的调查仅限于少数个人的病例报告。虽然已经报道了PLS的一些免疫异常，但缺乏标准化的方法使得很难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的原因。了解这种疾病的生物学基础的一个更好的策略是首先确定导致PLS的基因和相关突变。最近，一个PLS基因被报道定位在染色体11q的8- 10cm区域。我们还独立地将PLS基因定位在染色体11q上。我们研究了10个具有PLS的近亲家庭，使用纯合定位将PLS基因亚定位到染色体11q的4-5 cM区域。到目前为止，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。我们已经确定了另外10个有PLS的近亲家庭。这20个PLS家庭代表了迄今为止研究过的最大的PLS人口。我们提出了三种广泛的策略来确定导致PLS的基因突变。我们将继续进行基因定位研究，以进一步完善PLS基因的遗传候选区域（具体目标1）。我们建议通过分子研究来解决候选区域的物理和遗传图谱，以帮助确定PLS位点的候选基因和ESTs （Specific Aim number 2）。然后将使用基因鉴定和突变分析策略来评估基因并确定这些家庭中导致PLS的特定突变（具体目标3）。这些特定目标的完成将使我们能够确定负责PLS的基因，并为了解其生物学基础提供重要信息。确定PLS的遗传基础对PLS的诊断和治疗具有重要意义，并可能深入了解其他形式的牙周病对牙周破坏的易感性增加，特别是对治疗反应较差的严重牙周病。