P-0 glycoprotein overexpression causes congenital hypomyelination of peripheral nerves

We show that normal peripheral nerve myelination depends on strict dosage o f the most abundantly expressed myelin gene, myelin protein zero (Mpz). Tra nsgenic mice containing extra copies of Mpz manifested a dose-dependent, dy smyelinating neuropathy, ranging from transient perinatal hypomyelination t o arrested myelination and impaired sorting of axons by Schwann cells. Myel ination was restored by breeding the transgene into the Mpz-null background , demonstrating that dysmyelination does not result from a structural alter ation or Schwann cell-extrinsic effect of the transgenic P-o glycoprotein. Mpz mRNA overexpression ranged from 30-700%, whereas an increased level of P-o protein was detected only in nerves of low copy-number animals. Breedin g experiments placed the threshold for dysmyelination between 30 and 80% Mp z overexpression. These data reveal new points in nerve development at whic h Schwann cells are susceptible to increased gene dosage, and suggest a nov el basis for hereditary neuropathy.