NEUROFIBROMATOSIS--MOLECULAR-GENETIC APPROACH

神经纤维瘤病--分子遗传学方法

• 批准号: 3084470
• 负责人: Stefan M. PULST
• 金额: $ 8.63万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3084470
• 关键词: DNA; RNA; achondroplasia; alleles; autosomal dominant trait; chromosome deletion; chromosome translocation; electrophoresis; gel electrophoresis; gene expression; gene rearrangement; genetic disorder diagnosis; genetic mapping; genetic recombination; human genetic material tag; human population genetics; human subject; hybrid cells; in situ hybridization; karyotype; linkage mapping; mental retardation; messenger RNA; molecular pathology; neoplastic cell culture for noncancer research; neoplastic growth; neurofibromatosis; nucleic acid hybridization; polymerase chain reaction; restriction fragment length polymorphism

Von Recklinghausen-Neurofibromatosis (NF1) is one of the most common autosomal dominant Mendelian disorders affecting man. It is also the most common inherited predisposition toward tumor formation in man. The gene for NF1 has recently been the location further refined by the observation of NF patients with translocations involving chromosome 17. The study of patients with chromosome deletions may greatly aid int he identification of the NF1 gene. These patients are clinically recognized by the occurrence of several inherited conditions in one individual often accompanied by mental retardation. Three such patients have been identified. Two patients are mentally retarded and have a de novo occurrence of NF1 and achondroplasia (ACH). Because the chance association of these two diseases would be approximately 1 in 700 million, this suggests that these two diseases may be caused by a small deletion on chromosome 17. A third mentally retarded patient has NF1 and a cytogenetically visible deletion of chromosome 17. The proposed research has four specific aims directed towards analysis of the NF1 locus: 1) Identification of missing DNA sequences from patient with putative deletions by quantitative Southern blotting and pulsed-field gel electrophoresis using single copy DNA sequences tightly linked to the NF1 locus. 2) Elucidation of possible mechanisms of tumor formation in tumor cell lines established from NF1 benign and malignant tumors by analysis for loss of chromosomal material and loss of heterozygosity. 3) Development of novel techniques for identifying small chromosomal deletions using the analysis of hybrid cell lines containing a single chromosome 17 with interspersed repeated DNA sequences. This strategy could have major implications for the analysis of constitutional or somatic deletions in other diseases, for example NF2. 4) Molecular analysis of the mutation(s) causing Familial Spinal Neurofibromatosis by analysis of two families with autosomal dominant spinal neurofibromas. These families have shown linkage to the NF1 locus in preliminary studies. The sequence analysis of these mutation(s) may uniquely contribute to our understanding of tumorigenesis in NF1. These studies will contribute towards elucidating the molecular basis of NF1 mutations.

冯·雷克林豪森神经纤维瘤病 (NF1) 是最常见的一种 影响人类的常染色体显性孟德尔遗传病。 这也是最 人类肿瘤形成的常见遗传倾向。该基因为 最近通过对 NF 的观测进一步细化了 NF1 的位置 涉及 17 号染色体易位的患者。研究 染色体缺失的患者可能会极大地帮助识别 NF1基因。 这些患者在临床上是通过发生的事件来识别的 一个人身上的几种遗传性疾病通常伴随着 智力低下。 已确定三名此类患者。 二 患者智力低下，并重新出现 NF1 和 软骨发育不全（ACH）。 因为这两种疾病的偶然关联 大约是七亿分之一，这表明这两个 疾病可能是由 17 号染色体上的一个小缺失引起的。 智力迟钝患者患有 NF1 和细胞遗传学上可见的缺失 染色体17。拟议的研究有四个具体目标 NF1 位点分析：1) 缺失 DNA 的鉴定 通过定量Southern分析推测具有缺失的患者的序列 使用单拷贝 DNA 进行印迹和脉冲场凝胶电泳 与 NF1 位点紧密连锁的序列。 2) 解释可能的情况 NF1 建立的肿瘤细胞系中肿瘤形成的机制 通过分析染色体物质的丢失来诊断良性和恶性肿瘤 和杂合性的丧失。 3) 新技术的开发 使用杂交细胞分析识别小的染色体缺失 含有单个 17 号染色体且散布有重复 DNA 的品系 序列。 该策略可能对分析产生重大影响 其他疾病中的体细胞缺失，例如 NF2。 4） 引起家族性脊柱突变的分子分析 神经纤维瘤病两个常染色体显性遗传家系的分析 脊髓神经纤维瘤。 这些家族已显示出与 NF1 基因座的连锁 在初步研究中。 这些突变的序列分析可能 有助于我们了解 NF1 肿瘤发生。 这些研究将有助于阐明其分子基础 NF1突变。