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: 6362938
• 负责人: Thomas C Hart
• 金额: $ 19.29万
• 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 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362938
• 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，我们建议确定负责Papillon Lefevre综合征（PLS）的基因突变。 PLS是一种遗传性疾病，其特征是弥漫性跨性棕榈性角化病和严重的早期发作牙周炎，导致落叶和永久性牙齿过早丧失。 PL的治疗，特别是牙科成分的治疗，很困难且成功有限。 PLS继承为简单的常染色体隐性门德尔特征。尚未确定负责PL的基因，并且PLS的分子基础尚不清楚。 迄今为止，对PL的原因的调查仅限于少量个人的病例报告。 尽管已经报道了许多PL的免疫异常，但缺乏标准化方法使得很难推断各种研究的结果，并应用此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。 理解该疾病的生物学基础的更好策略是首先识别负责PL的基因和相关的突变。最近，据报道，PLS基因位于染色体11q的8-10 cm区域。 我们还独立地将PL的基因定位为11q染色体。 我们使用纯合性映射研究了10个具有PLS的血统家族，以将PLS基因转向染色体11q的4-5 cm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。 我们已经确定了另外10个与PLS的血统家庭。 这20个PLS家族是有史以来最大的PLS人群。 我们提出了3种广泛的策略，以确定负责PL的基因突变。 我们将继续基因映射研究，以进一步完善PLS基因的遗传候选区域（特定目的编号1）。 我们建议分子研究解决候选区域的物理和遗传图，以帮助鉴定PLS基因座的候选基因和EST（特定目的编号2）。 然后，将使用基因鉴定和突变分析的策略来评估基因并确定负责这些家族中PL的特定突变（特定目的编号3）。这些特定目标的完成应使我们能够确定负责PL的基因，并提供重要的信息以了解其生物学基础。 PLS的遗传基础的识别对PLS的诊断和治疗具有影响，并可能会深入了解其他形式的牙周疾病对牙周销毁的易感性增加，尤其是对治疗反应较低的严重类型。

项目成果

An integrated physical and genetic map of the PLS locus interval on chromosome 11q14.

染色体 11q14 上 PLS 基因座区间的综合物理和遗传图谱。

• DOI: 10.1007/s003350010046
• 发表时间: 2000
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Hart,TC;Walker,SJ;Bowden,DW;Hart,PS;Callison,SA;Bobby,PL;Firatli,E
• 通讯作者: Firatli,E