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中文摘要
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我们建议克隆并表征负责门克斯的基因 综合症。 Menkes 综合征是一种 X 连锁隐性铜障碍 代谢特征为早期生长迟缓和严重 神经功能障碍。 该病尚无有效治疗方法 其生化水平的确切原因尚不清楚。 最近,一个 患有该疾病且存在从头 X 常染色体易位的女性 确定。 Xql3 处的易位断点与先前的易位断点重合 Menkes 基因座的连锁分配和可能的位置 小鼠体内的同源斑驳基因座。 因此几乎可以肯定 破坏门克斯综合征基因的正常表达,并且很可能 直接打断它。 我们的克隆策略是基于物理 在此易位处 DNA 序列的鉴定和克隆 断点。 易位断点的位置相对于许多 Xql3 探针已通过利用体细胞杂交体确定 含有易位染色体。 发现易位 断裂靠近 PGK-1 位点的 X 染色体。 有了这个 知识,开始绘制该地区的长距离物理地图,试图 检测易位断点。 发现断点在 Sfil 消化的 DNA 上的 300kb PGK-1 基因座。 已经开始努力 以获得跨越该区域的酵母人工染色体(YACS)。 在 在这个修改后的应用程序中,我们建议识别跨域的 YAC 克隆 门克斯综合征易位断点并且很可能包含 来自门克斯综合征基因内部或与门克斯综合征基因密切相关的序列。 一个 将绘制该地区的实物图并确定 CpG 岛屿。 总 YAC 和 lambda 亚克隆都将用于筛选 cDNA 文库 用于识别候选基因。 候选克隆将用于 分析门克斯综合征患者和斑驳小鼠的 DNA 和 RNA 突变。 该基因将通过序列分析来表征, 在不同组织中的表达,并可能通过表达研究 体外。门克斯易位提供了宝贵的资源 该基因的“路标”,是少数 X 连锁和常染色体基因之一 人类疾病基因位点的易位可用于此研究 善良。 拟议的研究不仅应该有助于更好地理解 门克斯综合征的基本缺陷,以及有关的新发现 铜代谢的一般情况。
英文摘要
We propose to clone and characterize the gene responsible for Menkes syndrome. Menkes syndrome is an X-linked recessive disorder of copper metabolism characterized by early growth retardation and severe neurological impairment. There is no effective treatment for the disease and its exact cause at the biochemical level is unknown. Recently, a female with the disease and a de novo X-autosome translocation was identified. The translocation breakpoint at Xql3 coincides with a previous linkage assignment of the Menkes locus and with the probable location of the homologous mottled locus in the mouse. It therefore almost certainly disrupts proper expression of the Menkes syndrome gene and may very likely directly interrupt it. Our cloning strategy is based on the physical identification and cloning of DNA sequences at this translocation breakpoint. The location of the translocation breakpoint with respect to a number of Xql3 probes has been determined by utilizing somatic cell hybrids containing the translocation chromosome. The translocation was found to break the X chromosome just proximal to the PGK-1 locus. With this knowledge, a long range physical map of the region was begun in attempt to detect the translocation breakpoint. The breakpoint was found to be within 300kb of the PGK-1 locus on Sfil digested DNA. Efforts have been initiated to obtain yeast artificial chromosomes (YACS) that span this region. In this revised application, we propose to identify YAC clones that cross the Menkes syndrome translocation breakpoint and will very likely contain sequences from within or closely linked to the Menkes syndrome gene. A physical map of the region will be constructed and CpG islands identified. Both total YACs and lambda subclones will be used to screen cDNA libraries for identification of candidate genes. Candidate clones will be used to analyze DNA and RNA from Menkes syndrome patients and from mottled mice for mutations. The gene will be characterized by sequence analysis, expression in different tissues and possibly by expression studies in vitro. The Menkes translocation provides an invaluable resource as a "signpost" for the gene and is one of but a few X-linked and autosomal translocations at a human disease gene locus available for studies of this kind. The proposed studies should not only lead to better understanding of the basic defect in Menkes syndrome, but also to new findings concerning copper metabolism in general.
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