Electron micrograph of sciatic nerve. Courtesy of J. Milbrandt, Washington University, St. Louis, Missouri, USA.

Many demyelinating diseases have a genetic basis. Although some of these disorders are associated with mutations in myelin proteins such as myelin protein zero and periaxin, this is not always the case. For example, mutations in the transcription factor EGR2 are found in some patients with inherited peripheral neuropathies. Intriguingly, these neuropathies are transmitted in a dominant manner but mice heterozygous for an Egr2 null allele are normal. This observation prompted the suggestion that the mutant EGR2 gene encodes a dominant-negative mutant protein in people with the disease. But as Nagarajan et al. report in Neuron, testing this seemingly straightforward hypothesis has led to deeper, unanticipated insights into the mechanisms behind these demyelinating diseases.

The authors first used a conventional approach to test whether mutant Egr2 acted as a dominant-negative inhibitor and could block the expression of a reporter gene. As the results were negative, they wondered whether any dominant-negative activity of the mutant transcription factor would only become manifest if the target genes were in their endogenous loci. However, to explore this idea required the previous identification of Egr2 targets. So the authors used microarray expression profiling of Schwann cells to identify genes induced by Egr2 expression, and found that several myelin genes were under the control of this transcription factor. Now, when they tested the effect of mutant Egr2 on the expression of these myelin genes in Schwann cells, Nagarajan et al. observed the dominant-negative activity that they had originally tried to find.

So, an inability of the Schwann cells to produce critical myelin proteins and execute the myelination programme seems to be at the core of the inherited peripheral neuropathies. Importantly, Nagarajan et al. obtained evidence that reintroducing the normal Egr2 gene to cells that express low levels of the protein can lead to the expression of the missing myelin proteins. This finding raises the possibility that the myelination defect might be reversible and opens new avenues for the development of therapeutic measures to treat these debilitating disorders.