Background: Hereditary neuropathy with liability to pressure palsies (HNPP) in most cases is caused by a deletion in chromosome 17p11.2-12 or, rarely, mutations resulting in a functional loss of one copy of the peripheral myelin protein 22 (PMP22) gene. Point mutations that lie deep within transmembrane (TM) domains causing major structural changes in PMP22 are associated with severe neuropathy.
Methods: A 25-year-old asymptomatic woman with a normal neurologic examination volunteered as a control subject. Electrophysiologic studies showed multiple entrapment neuropathies, prompting a search for a genetic defect. In addition, sural nerve fascicles from the subject were grafted into the cut ends of the sciatic nerve of nude mice and studied at 2, 6, and 8 weeks and compared with controls.
Results: Direct sequencing of the PMP22 gene revealed a G-->A transition at position 202 in axon 3 of the PMP22 gene. To determine if this was a causative mutation rather than a polymorphism, 102 DNA samples from controls were studied; none showed a similar base pair change. In the nerve xenografts, there was a marked delay at the onset of myelination and an impairment in the regenerative capacity of the nude mice axons engulfed by the mutant human Schwann cells. The axon tips were enlarged and demonstrated neurofilament density increase. Neurofilament density distribution histograms were bimodal in xenografts as well as in the subject's sural nerve.
Conclusion: This study provides unequivocal evidence that a base pair change causing a Val30Met substitution at the junction of the first TM domain and the extracellular loop of PMP22 results in the HNPP phenotype.