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 genetically heterogeneous group of polyneuropathies. Two major types can be distinguished based on electrophysiologic phenotypes: CMT type 1 (CMT1) displays uniformly decreased nerve conduction velocity associated with a demyelinating hypertrophic neuropathy, and CMT type 2 (CMT2) displays normal or near-normal nerve conduction velocity associated with a neuronal 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 molecular mechanisms leading to CMT1A. DNA duplication of a 1.5-Mb region is associated with CMT1A in the majority of cases. A defined segmental DNA duplication that cosegregates with a disease in a dominant Mendelian pattern had been unprecedented. A candidate gene for CMT1A, PMP22, which maps within the duplication and encodes a myelin-specific protein, was identified from studies on the trembler and tremblerJ mouse models for CMT. Point mutations in PMP22 have since been identified in cases of familial, non-duplication CMT1A. The genetic data presents two alternative molecular mechanisms involving the PMP22 gene that result in the same clinical and electrophysiologic phenotype of CMT1A. The impact of the underlying molecular mechanisms on the prospects for therapeutic development are discussed.