FUNCTIONAL GENOMICS OF A DEAFNESS/BLINDNESS SYNDROME

描述：常染色体亚瑟综合征1C型的致病基因 隐性遗传性耳聋/失明综合征，先前由 标记D11S861与899的遗传连锁分析少校 本研究的重点是克隆和鉴定USH1C基因及其 产品，提供有关潜在病理生理的关键信息 这种和其他形式的双重神经感觉综合征的机制。自.以来 该区域被发现对使用YAC(酵母)进行克隆是困难的 人工染色体)载体，一种P1人工染色体(PAC) 构建了重叠群。包含临界区的400kb重叠群 正在为使用外显子陷阱cDNA进行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起 新的转录单位，我们已经确定并映射到 临界区。目前的建议是针对(1)确定 关键区域的转录单位；(2)分析cDNA以确定 代表耐人寻味的候选基因；(3)检查患者的DNA 通过测序来识别基因的突变；以及(4)表征 基因及其产物在组织和细胞水平。因为表型 因为Usher类型1C与其他五个USH1基因座是无法区分的，这 研究可能会对导致深远影响的机制有深入的了解 耳聋、前庭功能障碍和进行性视网膜变性 提供了对导致大多数 出生时患有双重神经感觉变性的儿童。

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.