A Transgenic Mouse Model for Human Hereditary Neuropathy with Liability to Pressure Palsies Peter R. Maycox,* ,1 Daniel Ortun ˜ o,* Patrick Burrola,* Rainer Kuhn,* ,2 Phyllis L. Bieri,² Joseph C. Arrezo,² and Greg Lemke* * Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037; and † Department of Neurology, Albert Einstein College of Medicine, New York, New York 10461 Mutations in the gene encoding peripheral myelin protein 22 (PMP22) account for several inherited peripheral neurop- athies in humans. We now show that transgenic mice expressing antisense PMP22 RNA exhibit modestly re- duced levels of PMP22 together with a phenotype that is reminiscent of hereditary neuropathy with liability to pres- sure palsies (HNPP), a human disease caused by a 1.5-Mb deletion of a chromosome 17 region that contains the PMP22 gene. Transgenic antisense homozygotes display a striking movement disorder and a slowing of nerve conduction that worsens with age. Morphological analysis of peripheral nerves demonstrates that a subset of axons have thickened myelin sheaths and tomacula in young adults, with significant myelin degeneration detected in older animals. Together with other recent work, these data suggest that dosage of the PMP22 gene alone underlies the pathophysiology observed in HNPP and related disor- ders. INTRODUCTION The myelin sheath is a spirally wrapped organelle that surrounds many peripheral and central axons in vertebrates, allowing rapid, saltatory conduction of neuronal action potentials (Lemke, 1992). In the PNS, myelin is elaborated by Schwann cells, and in the CNS, it is elaborated by oligodendrocytes. While a subset of proteins is common to both central and peripheral myelin, specific proteins are preferentially expressed in either the CNS (e.g., the proteolipid protein, PLP) or the periphery (e.g., protein zero, P 0 ) (Lemke, 1992). Among the latter is peripheral myelin protein 22 (PMP22), a 22-kDa glycoprotein largely restricted to the compacted regions of the PNS myelin sheath. An integral mem- brane protein with four predicted transmembrane do- mains, PMP22 is related in its secondary structure to gap junction connexins and other tetraspan proteins, including PLP (Schneider et al., 1988; Spreyer et al., 1991; Welcher et al., 1991; Suter and Snipes, 1995). Although myelinating Schwann cells are the most prominent site of PMP22 expression, the protein is also expressed in some nonneural tissues during development and in the adult, and it is expressed in motor neurons of the cranial nerve motor nuclei and in the anterior horn of the spinal cord (Parmantier et al., 1993). The particularly high levels of expression observed in myelinating Schwann cells are thought to be due to the influence of a strong Schwann cell-specific alernative PMP22 promoter (Suter et al., 1994). Although the function of PMP22 is unclear, it may multimerize to form a channel or pore for ions or small metabolites. Recent data suggest that it is essential to myelin structural stability (Adlkofer et al., 1995) and that it may also induce growth arrest in Schwann cells (Zoidl et al., 1994). PMP22 has been directly implicated in several domi- nantly inherited peripheral neuropathies, which are among the most common of inherited diseases in hu- mans (Suter and Snipes, 1995). The PMP22 gene is located at chromosome 17p11.2–p12, in a 1.5-Mb region (Matsunami et al., 1992; Patel et al., 1992; Timmerman et al., 1992) that undergoes either intrachromosomal dupli- cation in the case of Charcot–Marie–Tooth disease type 1A (CMT1A) (Lupski et al., 1991) or intrachromosomal deletion in the case of hereditary neuropathy with 1 Present address: Department of Molecular Neuropathology, Smith- Kline Beecham, Harlow, UK. 2 Present address: Department of Biotechnology, Ciba-Geigy Ltd., Basel, Switzerland. MCN Molecular and Cellular Neuroscience 8, 405–416 (1997) Article No. CN970600 405 1044-7431/97 $25.00 Copyright r 1997 by Academic Press All rights of reproduction in any form reserved.