MOLECULAR ANALYSIS OF HUMAN CHROMOSOME 17

人类 17 号染色体的分子分析

• 批准号: 3318897
• 负责人: David H. Ledbetter
• 金额: $ 16.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1994-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3318897
• 关键词: DNA directed DNA polymerase; Prader Willi syndrome; autosomal recessive trait; biochemical evolution; brain disorders; chromosome deletion; chromosome translocation; clone cells; complementary DNA; cytogenetics; gel filtration chromatography; gene mutation; gene rearrangement; genetic disorder; genetic disorder diagnosis; genetic library; genetic manipulation; genetic mapping; genetic markers; genome; human population genetics; human subject; hybrid cells; in situ hybridization; linkage mapping; meiosis; molecular cloning; molecular pathology; neurologic manifestations; nucleic acid hybridization; nucleic acid probes; nucleic acid sequence; point mutation; syndrome; transposon /insertion element

Miller-Dieker syndrome (MDS) is s contiguous gene syndrome comprised of a severe neuronal migration disorder producing type I lissencephaly (smooth brain, argyria), characteristic dysmorphic features, and other congenital abnormalities. It is caused by a cytogenetic microdeletion in about half of cases, while the other half have recently been shown by us to have submicroscopic deletions detected by anonymous DNA probes. MDS thus offers a model system for the reverse genetics cloning of genes involved in the pathogenesis of a complex disease phenotype, and a more basic understanding of mechanisms of cytogenetic disorders and normal corticogenesis. Specific goals of the project include: 1) improved diagnostic ability in MDS by identification of new DNA probes in the critical region, additional RFLPs, and development of rapid RFLP analysis by the polymerase chain reaction (PCR). We will also determine whether patients with isolated lissencephaly syndrome (ILS), without the dysmorphic features of MDS, also have deletions or other alterations of a locus on 17p. 2) Study of mechanisms of chromosome rearrangement by determination of parental origin of rearrangements, pulsed-field detection of deletion and translocation breakpoints, followed by strategies to clone and sequence the breakpoint junctions. 3) Search for candidate genes by identification of evolutionarily conserved sequences and HTF islands, followed by search for RNA transcripts and identification of corresponding cDNA clones. 4) Contribute to human genome project and comparative mapping in man and mouse. A high- resolution regional mapping panel for 17p is being developed by addition of new patient breakpoints isolated in somatic cell hybrids, a long-range restriction map is being developed by pulsed- field gel analysis, and mapping in the mouse is being conducted by somatic cell hybrid techniques and by analysis of interspecific backcrosses between mus spretus and mus domesticus. We will determine whether MDS probes map close to known mouse neurological mutations, which may provide an animal model for MDS.

Miller-Dieker综合征（MDS）是S连续基因综合征 由严重的神经元迁移障碍组成 i lissencephaly（光滑的大脑，argyria），特征性畸形 特征和其他先天性异常。 它是由 大约一半的病例中的细胞遗传学微骨骼，而另一个 最近，我们已经证明了一半 通过匿名DNA探针检测到的缺失。 因此，MD提供了 涉及基因的反向遗传克隆的模型系统 复杂疾病表型的发病机理和更基础的 了解细胞遗传学疾病和正常机制 皮质发生。 该项目的具体目标包括：1） 通过识别新DNA的MDS诊断能力提高了 关键区域，其他RFLP和开发的探针 聚合酶链反应（PCR）快速RFLP分析。 我们 还将确定孤立的脑颅患者是否 综合征（ILS），没有MD的畸形特征，也有 删除或17便士基因座的其他变化。 2）研究 通过确定父母的染色体重排机制 重排的起源，脉冲场检测缺失和 易位断点，然后是克隆的策略和 序列断点连接。 3）搜索候选基因 通过鉴定进化保守的序列和HTF 岛屿，然后搜索RNA成绩单和识别 相应的cDNA克隆。 4）有助于人类基因组 人和鼠标的项目和比较映射。 高 - 为17p开发了17p的区域映射面板 在体细胞中分离的新患者断点的添加 杂种，脉冲 - 正在开发一个远程限制图 现场凝胶分析和小鼠中的映射正在通过 体细胞杂种技术和通过种间分析 Mus Spretus和Mus foreverus之间的反向交叉。 我们将 确定MDS探针是否映射接近已知的小鼠神经系统 突变，可能为MD提供动物模型。