Peripheral neuropathy in mice transgenic for a human MDR3 P-glycoprotein mini-gene.
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 phsopholipid 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.
Smit
J J
JJ
The Netherlands Cancer Institute, Division of Molecular Biology, Amsterdam, The Netherlands.
Baas
F
F
Hoogendijk
J E
JE
Jansen
G H
GH
van der Valk
M A
MA
Schinkel
A H
AH
Berns
A J
AJ
Acton
D
D
Nooter
K
K
Burger
H
H
Smith
S J
SJ
Borst
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics*; D000818:Animals; D002874:Chromosome Mapping; D006224:Cricetinae; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D010523:Peripheral Nervous System Diseases / Q000235:genetics*; D012583:Schwann Cells / Q000378:metabolism; D012584:Sciatic Nerve / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1