Neurogenetics: white matter matters

Abstract

A group of inherited syndromes characterized by progressive muscle weakness and atrophy and sensory dysfunction, collectively referred to as Charcot–Marie–Tooth disease (CMT), has proven to be a hotbed for the identification of novel genetic mutations. CMT syndromes are unusually common, affecting one in every 2200 people. They can be dominant, recessive or X-linked, and involve demyelination and axonal damage. In two recent articles, Baxter et al. [1] and Cuesta et al. [2] identify the genetic defect responsible for a novel recessive CMT syndrome called CMT4A. The defect responsible for CMT4A was mapped to chromosome 8, and mutations in the gene encoding ganglioside-induced differentiation-associated protein-1 (GDAP1) were established as the disease-causing alterations. GDAP1 is expressed in both the PNS and CNS where it can be present at particularly high levels in Schwann cells and oligodendrocytes; levels increase during development and are highest in the adult. GDAP1 encodes a protein with two transmembrane domains and a region that contains a glutathione S transferase (GST) domain. GSTs are known to function in antioxidant pathways and in detoxification, and GDAP1 appears to contain a glutathione-binding site in a thioredoxin-like fold domain adjacent to an alpha-helical domain that might recognize xenobiotic substrates. Its presumptive antioxidant/detoxification properties might play a role in protecting myelin membranes against free radical-mediated damage, to which they are susceptible.