MOLECULAR STUDIES IN C/M/T DISEASE TYPE 4 B AND C

Charcot-Marie-Tooth病(CMT)是一种常见的周围神经病， 不同的遗传方式和广泛的遗传异质性。 该分子的研究已取得重大进展。 常染色体显性遗传型缺陷导致的鉴定 几种周围神经蛋白(PMP-22、PO和连接蛋白32)。目标是 这项提议的目的是使用类似的位置克隆技术来 鉴定两种不同形式常染色体隐性遗传性CMT的缺陷 (CMT4B和C)。 我们之前收集了一大系列CMT4家族，并提出了 改进后的分类为A、B和C三种类型。 证明了一个组：CM4A与染色体8q21连锁。 随后，我们已经证明CMT4B和CMT4C不映射到这一点 染色体区域。 大型近交系CMT4B和CMT4C将进行染色体基因分型 使用连锁分析进行定位。一旦检测到链接，YAC 并将在整个地区启动PAC重叠群。使用重叠群， 我们将在该地区生成更多重复标记。钥匙 重组事件和连锁不平衡将被调查以 进一步缩小病情剥离间隔。直接选择 技术随后将被用来构建一个转录图谱 允许对候选基因进行突变测试的区域。

Charcot-Marie-Tooth disease (CMT) is a common peripheral neuropathy with different modes of inheritance and extensive genetic heterogeneity. Significant progress has been made in the elucidation of the molecular defects of autosomal dominant forms leading to the identification of several peripheral nerve proteins (PMP-22, PO, and Connexin 32). The goal of this proposal is to employ similar positional cloning techniques to identify the defects for two different forms of autosomal recessive CMT (CMT4B and C). We have previously collected a large series of CMT4 families and proposed an improved classification into three types A, B, and C. In addition, we demonstrated linkage of one group: CM4A to chromosome 8q21. Subsequently, we have shown that CMT4B and CMT4C do not map to this chromosomal region. Large inbred CMT4B and CMT4C families will be genotyped for chromosomal localization using linkage analysis. Once a linkage is detected, a YAC and a PAC contig will be initiated across the region. Using the contig, we will generate additional repeat markers in the region. Key recombination events and linkage disequilibrium will be investigated to further narrow the disease flaking interval. The Direct selection technique will subsequently be used to construct a transcription map in the region allowing for candidate genes to be tested for mutations.