A new ENU-induced allele of mouse quaking causes severe CNS dysmyelination

The mutant allelic series of the mouse quaking gene consists of the spontaneous quakingviable (qkv) allele, which is homozygous viable with a dysmyelination phenotype, and four ENU-induced alleles (qkkt1, qkk2, qkkt3/4, and qkl-1), which are homozygous embryonic lethal. Here we report the isolation of qke5, the first ENU-induced viable allele of quaking. Unlike qkv/qkv, qke5/qke5 animals have early-onset seizures, severe ataxia, and a dramatically reduced lifespan. Ultrastructural analysis of qke5/qke5 brains reveals severe dysmyelination when compared with both wild-type and qkv/qkv brains. In addition, Calbindin detection in young adult qke5/qke5 mice reveals Purkinje cell axonal swellings indicative of neurodegeneration , which is not seen in young adult qkv/qkv mice. Although the molecular defect in the qke5 allele is not evident by sequencing, protein expression studies show that qke5/qke5 postnatal oligodendrocytes lack the QKI-6 and QKI-7 isoforms and have reduced QKI-5 levels. The oligodendrocyte developmental markers PDGFαR, NG2, O4, CNP, and MBP are also present in the qke5/qke5 postnatal brain although CNP and MBP levels are considerably reduced. Because the qkv allele is a large deletion that affects the expression of three genes, the new neurologic qke5 allele is an important addition to this allelic series.