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Volume 16, Number 20, Issue of October 15, 1996 pp. 6386-6393
Copyright ©1996 Society for Neuroscience

Peripheral Neuropathy in Mice Transgenic for a Human MDR3 P-Glycoprotein Mini-Gene

Jaap J. M. Smit¹, Frank Baas⁵, Jessica E. Hoogendijk³, Gerard H. Jansen⁴, Martin A. van der Valk², Alfred H. Schinkel¹, Anton J. M. Berns², Dennis Acton², Kees Nooter⁶, Herman Burger⁶, Sander J. Smith¹, and Piet Borst¹

¹ The Netherlands Cancer Institute, Divisions of Molecular Biology and ² Molecular Genetics, 1066 CX Amsterdam, The Netherlands, ³ University Hospital Utrecht, Departments of Neurology and ⁴ Pathology, Subdivision of Neuropathology, 3508 GA Utrecht, The Netherlands, ⁵ Department of Neurology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands, and ⁶ Department of Oncology, University Hospital Rotterdam, 3015 GD Rotterdam, The Netherlands

We have generated mice transgenic for a human MDR3 mini-gene, under control of a hamster vimentin promoter. Expression of the MDR3 transgene was found in mesenchymal tissues, peripheral nerves, and the eye lens. These MDR3 transgenic mice have a slowed motor nerve conduction and dysmyelination of their peripheral nerves. An extensive dysmyelination in some transgenic strains results in a severe peripheral neuropathy with paresis of the hind legs. How expression of the MDR3 transgene causes these abnormalities is unknown. The MDR3 gene encodes a large glycosylated plasma membrane protein with multiple transmembrane spanning domains, which are involved in the translocation of the phospholipid phosphatidylcholine through the hepatocyte canalicular membrane. The ability of the MDR3 P-glycoprotein to alter phospholipid distribution in the plasma membrane of Schwann cells may cause the damage. It is also possible, however, that the presence of a large glycoprotein in the cell membrane may be sufficient to severely disturb myelination of peripheral nerves.

Key words: peripheral neuropathy; dysmyelination; vimentin promoter; transgenic mice; MDR3; P-glycoprotein

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