MOLECULAR-BASIS OF CHARCOT-MARIE-TOOTH DISEASE TYPE-1A - GENE DOSAGE AS A NOVEL MECHANISM FOR A COMMON AUTOSOMAL-DOMINANT CONDITION

Charcot-Marie-Tooth disease (CMT) comprises a clinically and genetical ly heterogeneous group of polyneuropathies. Two major types can be dis tinguished based on electrophysiologic phenotypes: CMT type 1 (CMT1) d isplays uniformly decreased nerve conduction velocity associated with a demyelinating hypertrophic neuropathy, and CMT type 2 (CMT2) display s normal or near-normal nerve conduction velocity associated with a ne uronal defect. Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common form, exhibiting autosomal dominant inheritance and linkage to chromosome 17p11.2p12. This review will focus on the underlying molec ular mechanisms leading to CMT1A. DNA duplication of a 1.5-Mb region i s associated with CMT1A in the majority of cases. A defined segmental DNA duplication that cosegregates with a disease in a dominant Mendeli an pattern had been unprecedented. A candidate gene for CMT1A, PMP22, which maps within the duplication and encodes a myelin-specific protei n, was identified from studies on the trembler and trembler(J) mouse m odels for CMT. Point mutations in PMP22 have since been identified in cases of familial, non-duplication CMT1A. The genetic data presents tw o alternative molecular mechanisms involving the PMP22 gene that resul t in the same clinical and electrophysiologic phenotype of CMT1A. The impact of the underlying molecular mechanisms on the prospects for the rapeutic development are discussed.