A NOVEL PMP22 POINT MUTATION CAUSING HNPP PHENOTYPE - STUDIES ON NERVE XENOGRAFTS

Background Hereditary neuropathy with liability to pressure palsies (H NPP) 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 de ep 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 a s a control subject. Electrophysiologic studies showed multiple entrap ment neuropathies, prompting a search for a genetic defect. In additio n, sural nerve fascicles from the subject were grafted into the cut en ds 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 ge ne 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 poly morphism, 102 DNA samples from controls were studied; none showed a si milar base pair change. In the nerve xenografts, there was a marked de lay at the onset of myelination and an impairment in the regenerative capacity of the nude mice axons engulfed by the mutant human Schwann c ells. The axon tips were enlarged and demonstrated neurofilament densi ty increase. Neurofilament density distribution histograms were bimoda l in xenografts as well as in the subject's sural nerve. Conclusion: T his study provides unequivocal evidence that a base pair change causin g a Val30Met substitution at the junction of the first TM domain and t he extracellular loop of PMP22 results in the HNPP phenotype.