Charcot-Marie-Tooth neuropathy (CMT) is a heterogeneous group of inherited disorders of peripheral nerve. CMT type 1 (CMT1) is a demyelinating neuropathy with loci that map to chromosome 1 (CMT1B), chromosome 17 (CMT1A), the X chromosome (CMTX), and other autosome(s) (CMT1C). CMT type 2 (CMT2) is an axonal neuropathy in which the genetic locus is unknown. Recurrent Pressure-Sensitive Neuropathy (RPSN), a related condition, is another demyelinating peripheral neuropathy and maps to chromosome 17. Using molecular methods, the genetic basis of RPSN and each of the types of CMT will be investigated. CMT 1A is associated with a DNA duplication in band 17p11.2. We have mapped RPSN to chromosome 17p11.2 and determined that this disorder results from a deletion of the same region which is duplicated in CMT1A. The mechanism through which the CMT1A duplication and the RPSN deletion are generated is unknown, however, these two disorders are apparently reciprocal deletion/ duplication syndromes resulting from unequal crossing-over. A candidate gene, peripheral myelin protein-22 (PMP-22) has been mapped to the duplicated/deleted region, and may cause the CMT1A phenotype through trisomic over-expression and the RPSN phenotype through under-expression. We will explore the molecular basis of CMT 1A and RPSN through cloning and characterization of the duplicated/deleted region on chromosome 17, including the duplication/deletion breakpoint junctions. A series of CMT1 and RPSN patients will be surveyed in order to determine the frequency and homogeneity of size and location of the duplications/deletions. Using DNA markers which closely flank and span the duplication/deletion, a continuous series (contig) of yeast artificial chromosome (YAC) clones encompassing the duplication will be identified. The duplication/deletion junction will be isolated, and used to search for homogeneity of breakpoint placement in a series of CMT1A and RPSN patients. The mechanism generating the duplication/deletion will be explored through sequencing the breakpoint junction region. PMP- 22 will be further investigated as a candidate gene by Northern analysis in CMT1A patients, and a search for point mutations in dominant CMT1 pedigrees without the duplication. The myelin PO gene which maps to chromosome 1 will be tested as a candidate gene for CMT1B, by a search for point mutations and by linkage analysis. The genetic basis of CMT1C and CMT2 will be investigated through linkage analysis with DNA markers from multiple autosomes. The CMTX locus will be fine-mapped by linkage analysis with markers from the proximal long arm of the X chromosome, and participation in a consortium for CMTX mapping.
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