Mice that lack a functional Prx gene ensheath and myelinate peripheral nerve axons in an apparently normal manner, but this sheath later destabilizes and the mice develop a severe demyelinating neuropathy. Hence, periaxins play an essential role in the establishment of a stable Schwann cell-axon unit in the myelinated fibers of the vertebrate peripheral nervous system. In addition to a marked reduction in their peripheral nerve conduction velocities, periaxin-null mice display reflex behaviours associated with neuropathic pain. Damage to sensory nerves in human peripheral demyelinating disease is also known to be to linked to pain and excessive sensitivity to touch. Segmental demyelination in human disease can be associated with tactile allodynia, the perception of normally innocuous stimuli such as touching or brushing as painful, and hyperalgesia, a heightened response to painful stimuli; however, the mechanisms of neuropathic pain in demyelinating disease are poorly understood. Several families have now been identified with a variant of Charcot-Marie-Tooth disease which we call CMT4F in which the periaxin gene is mutated. Recent progress in this area has been marked by our identification of a new dystroglycan complex in the Schwann cell plasma membrane in which periaxin is a key component. It seems that disruption of this complex is at the heart of the derangement of myelination observed in the periaxin KO mouse, and probably in the human disease. We are presently seeking to identify the other components of the complex since these may represent candidate genes for other types of CMT disease.

This work was supported by The Wellcome Trust.

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