Abstract

Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies. The underlying mutations in demyelinating forms tend to affect genes expressed in Schwann cells (CMT types 1, 3, and 4), while axonal forms of the disease usually have their origins in genes expressed in the affected neurons (CMT type 2). Repeated rounds of nerve degeneration and regeneration characterize CMT2, but evidence for regeneration has not been demonstrated at a molecular level. Subtractive hybridization was performed on sural nerve biopsies from a patient presenting an axonal form of CMT and an unaffected sibling, which revealed an overexpression of genes associated with the regeneration of axons, including PMP22, SPARC/osteonectin, CD9, CD44, EEF1A1, and gamma-actin. These results suggest that axonal degeneration elicits a regeneration transcriptional response in the surrounding Schwann cells. This response contrasts with other neurodegenerative diseases, in which programmed cell death or an inappropriate immune response are activated. Additionally, Lamin A/C, which is mutated in CMT2B1, was overexpressed in the patient, suggesting that CMT-causing genes may interact in a regulatory network.