PATHOGENESIS OF CONGENITAL HYPOMYELINATION REVEALED BY P0 OVEREXPRESSING MICE

Abstract

Extra copies of the myelin protein zero (Mpz) gene cause dysmyelinating neuropathy in transgenic mice. Clinical and pathological findings are dose dependent, ranging from transient perinatal hypomyelination (30% mRNA overexpression), to arrested nerve development with impaired sorting of axons by Schwann cells (700% mRNA overexpression). Mpz overexpression promotes inappropriate trafficking of P0 protein to surface membranes of promyelinating Schwann cells. Ultrastructural immunocytochemistry demonstrates that mistargeting of P0 to the membranes of the advancing mesaxon (the lip of Schwann cell membrane that enwraps the axon) activates P0 homophilic adhesion, arresting spiral wrapping and myelination.Severely reduced nerve conduction velocities, paucity of active myelin destruction or onion bulbs, and redundant basement membrane formation in P0‐overexpressor mice resemble those present in human congenital hypomyelination (CHN). CHN is a subtype of demyelinating neuropathy due to MPZ mutation. Although increased MPZ has not yet been described in CHN, increased myelin gene dosage (PMP22 and PLP) can cause hereditary myelinopathy in both rodent and human (Charcot‐Marie‐Tooth IA and Pelitzaus Merzbacher disease). Of note, mutations in the Krox 20 transcription factor, encoded by EGR2, are also associated with CHN. Since one of these EGR2 mutations likely disinhibits Krox 20, and Krox 20 may regulate P0 expression, it is possible that MPZ overexpression contributes to the pathogenesis of this EGR2 mutation.