International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

E4 Correction of Neurological Phenotypes in Quaking by Introduction of a 160-kb BAC Transgene

T. Kondo1, T. Kaname1, Kanae Mitsunaga1, T. Ebersole2, K. Artzt3, K. Yamamura1 and Kuniya Abe1. 1Inst. Mol. Emb. Genet, Kumamoto Univ. Sch. Med.; 2Human Genetics Unit, Western General Hospital, UK; 3Dept. Zool., Univ. Texas at Austin

Mouse qkI gene, which encodes KH-domain containing RNA binding protein, was isolated as a candidate for quaking viable (qkv) mutation. qkI locates adjacent to, not within , a deletion spanning about 1 Mb in the genome of the qkv. qkv is a classical, recessive neurological mutation, showing rapid tremors when moving, and tonic-clonic type seizures. Such neurological phenotypes are thought to be due to hypomyelination in CNS of the affected mice. We have proven its candidacy by conducting a series of experiments including analyses of genomic organization and expression of the qkI (Kondo et al., Mamm Genome 10, 662-669, 1999), and a genetic complementation test with a targeted null allele. Compound heterozygotes between qkv and a knockout allele, qkIo showed the neurological phenotypes. qkv appears to be a hypomorph, as levels of all the transcripts from the qkI locus are significantly reduced, and was even less in the compound, qkv /qkI0 . qkI regulates myelination in a dosage-dependent manner, since the qkv /qkI0 exhibited severer phenotypes than qkv/qkv. It is thus presumed that certain level of qkI expression is essential; once the qkI level becomes below the critical level,i.e. 30% of normal, myelination defects is manifested. To test this idea, we introduced normal copy of qkI gene into mutant animals to increase qkI expression. We established transgenic lines with a 160-kb BAC genomic clone containing the entire qkI gene, and crossed these mice with quaking mutants. The BAC construct successfully rescue the neurological phenotypes such as tremor, ataxic gate as well as growth retardation. This result excludes a possibility that other anonymous gene within the deletion is involved in the qk phenotype , and that myelination requires a certain level of qkI expression.


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