A mutation in the gene encoding mitochondrial Mg²+ channel MRS2 results in demyelination in the rat.
The rat demyelination (dmy) mutation serves as a unique model system to investigate the maintenance of myelin, because it provokes severe myelin breakdown in the central nervous system (CNS) after normal postnatal completion of myelination. Here, we report the molecular characterization of this mutation and discuss the possible pathomechanisms underlying demyelination. By positional cloning, we found that a G-to-A transition, 177 bp downstream of exon 3 of the Mrs2 (MRS2 magnesium homeostasis factor (Saccharomyces cerevisiae)) gene, generated a novel splice acceptor site which resulted in functional inactivation of the mutant allele. Transgenic rescue with wild-type Mrs2-cDNA validated our findings. Mrs2 encodes an essential component of the major Mg²+ influx system in mitochondria of yeast as well as human cells. We showed that the dmy/dmy rats have major mitochondrial deficits with a markedly elevated lactic acid concentration in the cerebrospinal fluid, a 60% reduction in ATP, and increased numbers of mitochondria in the swollen cytoplasm of oligodendrocytes. MRS2-GFP recombinant BAC transgenic rats showed that MRS2 was dominantly expressed in neurons rather than oligodendrocytes and was ultrastructurally observed in the inner membrane of mitochondria. Our observations led to the conclusion that dmy/dmy rats suffer from a mitochondrial disease and that the maintenance of myelin has a different mechanism from its initial production. They also established that Mg²+ homeostasis in CNS mitochondria is essential for the maintenance of myelin.
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Kyoto, Japan. tkuramot@anim.med.kyoto-u.ac.jp
Takashi
T
Kuramoto
Mitsuru
M
Kuwamura
Satoko
S
Tokuda
Takeshi
T
Izawa
Yoshifumi
Y
Nakane
Kazuhiro
K
Kitada
Masaharu
M
Akao
Jean-Louis
JL
Guénet
Tadao
T
Serikawa
D000818:Animals; D030801:Animals, Genetically Modified; D027682:Cation Transport Proteins / Q000235:genetics* / Q000378:metabolism; D003711:Demyelinating Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008854:Microscopy, Electron; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D022821:RNA Splice Sites; D051381:Rats
D027682:Cation Transport Proteins; C556671:MRS2 protein, rat; D024101:Mitochondrial Proteins; D022821:RNA Splice Sites
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