MOLECULAR GENETIC STUDIES OF GLYCEROL KINASE DEFICIENCY

甘油激酶缺陷的分子遗传学研究

• 批准号: 2198576
• 负责人: Edward R B McCabe
• 金额: $ 4.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1994-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2198576
• 关键词: artificial chromosomes; chromosome complement; enzyme deficiency; gene deletion mutation; genetic markers; genetic recombination; genotype; glycerol kinase; human subject; inborn metabolism disorder diagnosis; laboratory rabbit; linkage mapping; messenger RNA; molecular cloning; molecular pathology; northern blottings; nucleic acid hybridization; nucleic acid probes; phenotype; polymerase chain reaction; pulsed field gel electrophoresis; southern blotting; tissue /cell culture

Glycerol kinase deficiency (GKD) maps to Xp21 and includes this enzyme deficiency as part of the contiguous gene syndrome, complex GKD, as well as of the juvenile (symptomatic with episodic vomiting, acidemia, and stupor) and adult (benign) forms of isolated GKD. Patients with complex GKD have interstitial deletions involving the GK as well as the adrenal hypoplasia congenita (AHC) and/or the Duchenne muscular dystrophy (DMD) loci, with patient phenotypes indicating the gene order: ter...AHC-GKD- DMD...cen. The continuing long term objective of this project is to understand the fundamental relationship between genotype and phenotype among individuals with GKD. Progress toward this objective has included developing yeast artificial chromosome (YAC) contigs in the region between C7 (DXS28) and DMD with only three small gaps; mapping of 28 markers in the region surrounding the AHC and GK loci; identification of deletion breakpoints in all patients with complex GKD including those who had no detectable deletion at the time of the original application; delineation of the specific interval that contains all or part of the GK gene; identification of a YAC insert that contains the entire GK critical region; and successful demonstration of a new method to scan genomic DNA for expressed sequences by establishing the presence of the X-linked human ferritin light chain (FTL) sequence on a cosmid in this region. The objective of improved understanding of genotype-phenotype relationships in patients with GKD will be pursued through the following Specific Aims: (1) Complete the contig in the region surrounding the AHC and GK loci using YACs and cosmids; (2) Clone and characterize expressed sequences in this region of Xp21; and (3) Identify mechanisms responsible for mutations in patients with complex GKD, isolated GKD and isolated involvement of other genes in this region such as AHC. These investigations will test the hypotheses that: (1) Availability of cloned genomic material will facilitate identification of expressed sequences in patients with complex GKD; (20 Individual expressed sequences will correlate with specific phenotypic features in patients with contiguous gene syndromes as well as isolated deficiencies; and (30 Improved information on genomic and expressed sequences will permit identification of mutation mechanisms underlying complex and isolated GKD.

甘油激酶缺乏症（GKD）映射到XP21，包括此酶 缺乏作为连续基因综合征的一部分，复杂的GKD 从少年开始（有症状的呕吐，酸血症和 昏迷）和成人（良性）孤立的GKD。 复杂的患者 GKD具有涉及GK和肾上腺的间质缺失 隆起的兴奋（AHC）和/或Duchenne肌肉营养不良（DMD） 基因座，患者表型表示基因顺序：ter ... ahc-gkd- DMD ... Cen。 该项目的持续长期目标是了解 个体之间基因型与表型之间的基本关系 与GKD。 朝这个目标的进步包括开发酵母 C7（DXS28）和 DMD只有三个小空白；该地区28个标记的映射 围绕AHC和GK基因座；识别删除断点 在所有具有复杂GKD的患者中，包括无法检测到的患者 原始申请时删除；描述 包含GK基因的全部或部分的特定间隔； 识别包含整个GK关键的YAC插入物 地区;并成功证明了一种扫描基因组DNA的新方法 通过建立X连锁的存在来表达序列 该区域的宇宙上的人铁蛋白轻链（FTL）序列。 改善对基因型 - 表型的了解的目的 GKD患者的关系将通过以下 具体目的：（1）完成AHC周围区域的重叠群 和GK基因座使用Yac和Cosmids； （2）克隆和表征表达 XP21区域中的序列； （3）确定负责的机制 用于复杂GKD患者的突变，分离的GKD和分离 其他基因在该区域（例如AHC）的参与。 这些调查将检验以下假设：（1）可用性 克隆的基因组材料将促进表达的鉴定 复杂GKD患者的序列； （20个人表示 序列将与患者的特定表型特征相关 与连续的基因综合征以及孤立的缺陷；和（30 改进有关基因组和表达序列的信息将允许 鉴定复合物和孤立的突变机制 GKD。