Charcot-Marie Tooth disease 1A (CMT1A) is the most common human demyelinating neuropathy. The most common cause is duplication of a 1.5 Mb region of chromosome 17 which is flanked by 30kb repeat sequences called CMT1A-REP. Both inherited and de novo duplications have been observed. Substantial evidence suggests that this duplication is the result of unequal crossing over involving homologous recombination between misaligned CMT1A-REP sequences. The reciprocal recombination yields a 1.5 Mb deletion associated with the clinically distinct disease called hereditary neuropathy with liability to pressure palsy (HNPP). The molecular details of this recombination event remains unknown. The gene for peripheral myelin protein-22 (PMP22) maps within the region duplicated in CMT1A and deleted in HNPP, and the respective phenotypes result from trisomic over-expression and haplo-insufficiency, respectively. Point mutations in PMP22 can also cause CMT1A and Dejerine-Sottas syndrome. Mutations in 2 other genes, MPZ and Cx32 can also cause CMT1A and HNPP. In the majority of CMT1A subjects without the chromosome 17 duplication, no mutations in the 3 genes (PMP22, MPZ, and Cx32) have been identified.
The aims of this proposal are to delineate the molecular mechanisms for CMT and related demyelinating peripheral neuropathies. Hypotheses to be addressed involve mechanisms of reciprocal recombination events associated with deletions and duplications. Also the genes in the CMT1A other than PMP22 will be evaluated.
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