MOLECULAR GENETIC ANALYSIS OF LOWE'S SYNDROME

低眼球脑肾综合征(OCRL)是一种X连锁的先天性错误 原因不明的新陈代谢。受影响的男性智力迟缓，并有 先天性白内障和肾小管功能障碍。OCRL的轨迹有 通过与限制片段长度连锁被映射到Xq25区域 Xq24-26基因的多态性与女性OCRL的发生 X/3易位，断裂点在Xq25。一种人造酵母 含有100-120kb人类插入片段的染色体(YAC)在 另一个合作实验室，并提供给这个实验室。 这个YAC，Rs88，似乎包含来自两侧的序列 OCRL女性X；3易位的断裂点。vbl.使用 来自Rs88内的序列、Lambda中的重叠基因组序列或 余弦向量将被隔离，直到 已克隆断点。所有来自这一地区的DNA都将接受检测 它是否包含基于(I)保守性的候选基因的外显子 人与其他哺乳动物之间的核酸同源性，(Ii)表达 晶状体、肾脏、大脑和成纤维细胞的序列，(所有靶组织 OCRL)，(Iii)这些基因的突变、缺失或其他表现 OCRL先证者的推测外显子序列。当候选基因是 确认身份， (1)对其完整的mRNA序列和基因组结构进行了表征。 (2)导致这种疾病的突变将通过以下方式确定 猪瘟病毒DNA中该基因的外显子和内含子-外显子边界的测序 病人 (3)将产生针对基因产物的抗体并用于检测 表达基因的组织(S)和细胞和 基因产物的亚细胞定位。 (4)负责基因调控的启动子和增强子序列 表达将被识别。 长期目标是确定人类精神疾病的基因 通过它的位置而不是它的功能而引起的迟缓综合征 以确定基因和表达以及突变的特征 对人类的疾病负有责任。最终的目标是理解 基因产物是什么，基因缺陷是如何导致疾病的。

The oculocerebrorenal syndrome of Low (OCRL) is an X-linked inborn error of metabolism of unknown etiology. Affected males are retarded and have congenital cataracts and renal tubular dysfunction. The locus for OCRL has been mapped to the Xq25 region by linkage to restriction fragment length polymorphisms (RFLPs) in Xq24-26 and by the occurrence of OCRL in a female with an X/3 translocation with breakpoint at Xq25. A yeast artificial chromosome (YAC) containing a 100-120 kb human insert was isolated in another, collaborating laboratory and made available to this laboratory. This YAC, RS88, appears to contain sequences from either side of the breakpoint in the X;3 translocation in the female with OCRL. Using sequences from within RS88, overlapping genomic sequences in lambda or cosmid vectors will be isolated until the entire region around the breakpoint have been cloned. All DNA from this region will be tested for whether it contains exons of a candidate gene based on (i) conservation of nucleic acid homology between man and other mammals, (ii) expression of the sequence in lens, kidney, m brain and fibroblasts, (all target tissues for OCRL), (iii) demonstration of mutation, deletional or otherwise, of these putative exonic sequences in OCRL probands. When a candidate gene is identified, (1) its entire mRNA sequence and genomic structure will be characterized. (2) the mutations responsible for the disease will be determining by sequencing the exons and intron-exon boundaries of the gene in the DNA of patients (3) antibodies to the gene product will be raised and used to determine the tissue(s) in which the gene is expressed and the cellular and subcellular localization of the gene product. (4) the promoter and enhancer sequences responsible for control of gene expression will be identified. The long-term objective is to identify the gene for a human mental retardation syndrome through its location rather than its function and then to characterize the gene and in expression as well as the mutations responsible for the disease in man. The ultimate goal is to understand what the gene product is and how defects in the gene produce disease.