Human Molecular Genetics, 2000, Vol. 9, No. 5 821-828
© 2000 Oxford University Press
The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a
1Department of Human Genetics, 4708 Medical Science II, University of Michigan, Ann Arbor, MI 48109-0618, USA, 2Mammalian Genetics Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA, 3Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06520, USA and 4Department of Medicine, University of California, San Diego, CA 92093, USA
Exon shuffling is thought to be an important mechanism for evolution of new genes. Here we show that the mouse neurological mutation flailer (flr) expresses a novel gene that combines the promoter and first two exons of guanine nucleotide binding protein beta 5 (Gnb5) with the C-terminal exons of the closely linked Myosin 5A (MyoVA) gene (Myo5a). The flailer protein, which is expressed predominantly in brain, contains the N-terminal 83 amino acids of Gnb5 fused in-frame with the C-terminal 711 amino acids of MyoVA, including the globular tail domain that binds organelles for intracellular transport. Biochemical and genetic studies indicate that the flailer protein competes with wild-type MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkinje cells. The flailer protein thus has a dominant-negative mechanism of action with a recessive mode of inheritance due to the dependence of competitive binding on the ratio between mutant and wild-type proteins. The chromosomal arrangement of Myo5a upstream of Gnb5 is consistent with non-homologous recombination as the mutational mechanism. To our knowledge, flailer is the first example of a mammalian mutation caused by germ line exon shuffling between unrelated genes.
+ Present address: Department of Biochemistry, University of Hong Kong, 5 Sassoon Road, Hong Kong
§ To whom correspondence should be addressed. Tel: +1 734 763 5546; Fax: +1 734 763 9691; Email: meislerm@umich.edu
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