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

腓骨肌萎缩症（CMT）是一种常见的周围神经病变， 不同的遗传方式和广泛的遗传异质性。 在分子解析方面取得了重大进展， 常染色体显性形式的缺陷导致鉴定 几种外周神经蛋白（PMP-22、PO和连接蛋白32）。目标 该建议的一个重要方面是采用类似的定位克隆技术， 确定两种不同形式的常染色体隐性CMT的缺陷 （CMT 4 B和C）。 我们以前收集了大量的CMT 4家族，并提出了 A、B、C三种类型的改进分类。另外我们 证明了一组连锁：CM 4A染色体8 q21。 随后，我们证明了CMT 4 B和CMT 4C不映射到这个 染色体区域 将对大型近交CMT 4 B和CMT 4C家族进行染色体分型。 使用连锁分析进行定位。一旦检测到链接，YAC 并在整个区域启动PAC重叠群。使用重叠群， 我们将在该区域产生额外的重复标记。关键 将研究重组事件和连锁不平衡， 进一步缩小了病害剥落间隔。 直接选择 技术随后将用于构建转录图谱， 该区域允许候选基因被测试突变。

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.