Developmental genetic analysis of mouse dysmyelination mutant, quaking.

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A responsible gene for mouse mutation showing ataxic phenotype was sought and analyzed in order to understand the etiology of the ataxia. [Results] It was found that qkl gene was spanning about 70 kb of genomic region, and consists of at least 10 exons. It gives rise to six distinct transcripts encoding, theoretically, five different protein isoforms. Exons 1 through 4 are shared by all the transcripts, whereas coding exons and two distinct 3'-UTRs downstream to the exon 4 are differentially utilized. One isoform has a truncated KH domain and may act as an antagonist to the others. These mRNA appear to encode a putative RNA binding protein containing one KH motif required for RNA binding activity. We have made three lines of qkl knockout mouse, of which two were analyzed in detail. Mice heterozygous for the KO allele behave normally. However, double heterozygotes in combination with the original qk allele (=qkv) showed rapid tremor, clearly demonstrating that qkl gene is the responsibl … More e gene for the quaking mutation. Furthermore, this double heterozygote compound mice showed even more severe phenotype compared to the qkv/qkv mice ; early onset of convulsion, gait abnormality, or growth retardation. In many ways this phenotype resembles that of some of the human leukodystrophies. This severe phenotype is probably due to premature arrest of myelination : the oligodendrocyte processes fail to properly interact with the axons to form compacted myelin. qkl expression was found to be significantly reduced in qkv homozygotes and was even less in the compound, qkv/qklO.Thus myelination appears to be sensitive to the dosage of qkl. In fact, when qkl level is increased by introduction of BAG clone containing the whole qkl gene, the tremor phenotype was completely recovered. mRNA expression of other myelin genes including PLP, MBP were reduced in the qk mutants, and there were almost no protein products for these genes. Furthermore, mRNA splicing of MAG, PLP and probably MBP is altered by the reduced qkl expression. These results sugegst that qkl is an essential regulator of myelination in CNS, and probably plays important role in post-transcriptional regulation of the myelin genes. Less