Distinct disease mechanisms in peripheral neuropathies due to altered peripheral myelin protein 22 gene dosage or a Pmp22 point mutation

Point mutations affecting PMP22 can cause hereditary demyelinating and dysmyelinating peripheral neuropathies. In addition, duplication and deletion of PMP22 are associated with Charcot-Marie-Tooth disease Type 1A (CMT1A) and Hereditary Neuropathy with Liability to Pressure Palsy (HNPP), respectively. This study was designed to elucidate disease processes caused by misexpression of Pmp22 and, at the same time, to gain further information on the controversial molecular function of PMP22. To this end, we took advantage of the unique resource of a set of various Pnip22 mutant mice to carry out comparative expression profiling of mutant and wild-type sciatic nerves. Tissues derived from Pynp22(-/-) ('knockout'), Pmp22(tg) (increased Pmp22 copy number), and Trembler (Tr; point mutation in Pmp22) mutant mice were analyzed at two developmental stages: (i) at postnatal day (P)4, when normal myelination has just started and primary causative defects of the mutations are expected to be apparent, and (ii) at P60, with the goal of obtaining information on secondary disease effects. Interestingly, the three Pmp22 mutants exhibited distinct profiles of gene expression, suggesting different disease mechanisms. Increased expression of genes involved in cell cycle regulation and DNA replication is characteristic and specific for the early stage in Pnip22(-/-) mice, supporting a primary function of PMP22 in the regulation of Schwann cell proliferation. In the Tr mutant, a distinguishing feature is the high expression of stress response genes. Both Tr and Pinp22(tg) mice show strongly reduced expression of genes important for cholesterol synthesis at P4, a characteristic that is common to all three mutants at P60. Finally, we have identified a number of candidate genes that may play important roles in the disease process or in myelination per se. (c) 2004 Elsevier Inc. All rights reserved.