Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by peroneal and distal muscle atrophy at the extremities. Clinically homogenous, the disorder is separated into two types, CMT 1 and CMT 2. These two types can be differentiated pathologically and physiologically using Nerve Conduction Studies (NCS). We initially localized CMT la to chromosome 17 and have recently sublocalized this form to the 17pll.2 region of chromosome 17. This proposal describes an approach to continue our localization of CMT la. In addition, CMT2 families are identified through our work on CMT la. We also propose to apply linkage analysis to CMT 2 to determine chromosomal location of this disorder. The approach towards localizing the CMT la gene includes expansion of family data, identification of probes using existing libraries (chromosome 17 cosmid library, L4 microcell link library), and the development of new plasmid libraries from chromosome 17 radiation hybrids spanning this region. Multipoint linkage analysis will be used for further localization with these probes until close flanking markers are found. Application of current methodology such as PCR, STS, CA repeats, single strand conformation polymorphisms and nucleotide analog polymorphisms will be used with selected cloned markers to increase heterozygosity of these probes. As close-flanking markers are found, concurrent physical mapping using pulse field gel electrophoresis, cosmid, linkage and hopping libraries and yeast artificial chromosomes will be used to map the region surrounding the CMT la gene. Candidate probes can be screened against zoo blots and a peripheral nerve cDNA library. A similar approach will be applied when the gene for CMT 2 is located.
