FUNCTIONAL GENOMICS OF A DEAFNESS/BLINDNESS SYNDROME

描述：基因负责Usher综合征1C型，一个常染色体 遗传性耳聋/失明综合征，以前由 标记D11 S861和899之间的遗传连锁分析。 主要 该建议的重点是克隆USH 1C基因，并对其进行表征， 产品，提供有关基础病理生理学的关键信息 这种和其他形式的双重感觉神经综合征的机制。 以来 发现该区域难以用YAC（酵母）克隆 人工染色体）为基础的载体，P1-人工染色体（PAC） 构建重叠群。 包含关键区域的400 kb重叠群 为使用外显子捕获的基因搜寻提供基因组资源， 选择和直接测序。 我们目前正在调查几个 新的转录单位，我们已经确定和映射到 关键区域。 目前的建议旨在（1）确定 关键区域的转录单位;（2）分析cDNA以确定 代表有趣的候选基因;（3）检查患者DNA， 通过测序鉴定所述基因的突变，以及（4）表征所述突变， 基因及其产物在组织和细胞水平。 由于表型 Usher 1C型与其他5个USH 1基因座无明显区别， 这项研究可能会深入了解造成深刻影响的机制。 耳聋、前庭功能障碍和进行性视网膜变性， 提供了新的见解综合征负责大多数 患有双重感觉神经变性的孩子

DESCRIPTION: The gene responsible for Usher Syndrome Type 1C, an autosomal recessively inherited deafness/blindness syndrome, was previously mapped by genetic linkage analysis between the markers D11S861 and 899. The major focus of this proposal is to clone, and characterize the USH1C gene and its product, providing critical information on the underlying pathophysiological mechanism for this and other forms of dual neurosensory syndromes. Since this region was found to be refractory to cloning using YAC (yeast artificial chromosome) based vectors, a P1-artificial -chromosome (PAC) contig was constructed. The 400 kb contig encompassing the critical region is providing the genomic resources for a gene hunt using exon trapping, cDNA selection, and direct sequencing. We are currently investigating several new transcription units which we have identified and mapped into the critical region. The current proposal is directed at (1) identifying transcription units in the critical region; (2) analyzing cDNAs to determine which represent intriguing candidate genes; (3) examining patient DNA for mutations by sequencing to identify the gene, and; (4) characterizing the gene and its product at the tissue and cellular levels. Since the phenotype for Usher type 1C is indistinguishable with the other five USH1 loci, this study may yield insights into the mechanism responsible for profound deafness, vestibular dysfunction and progressive retinal degeneration and provide new insights into the syndrome responsible for the majority of children born with dual neurosensory degeneration.