The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a

Exon shuffling is thought to be an important mechanism for evolution of new genes. Here we show that the mouse neurological mutation flailer (flr) exp resses a novel gene that combines the promoter and first two exons of guani ne nucleotide binding protein beta 5 (Gnb5) with the C-terminal exons of th e closely linked Myosin 5A (MyoVA) gene (Myo5a), The flailer protein, which is expressed predominantly in brain, contains the N-terminal 83 amino acid s of Gnb5 fused in-frame with the C-terminal 711 amino acids of MyoVA, incl uding the globular tail domain that binds organelles for intracellular tran sport. Biochemical and genetic studies indicate that the flailer protein co mpetes with wild-type MyoVA in vivo, preventing the localization of smooth endoplasmic reticulum vesicles in the dendritic spines of cerebellar Purkin je cells. The flailer protein thus has a dominant-negative mechanism of act ion with a recessive mode of inheritance due to the dependence of competiti ve binding on the ratio between mutant and wild-type proteins. The chromoso mal arrangement of Myo5a upstream of Gnb5 is consistent with non-homologous recombination as the mutational mechanism. To our knowledge, flailer is th e first example of a mammalian mutation caused by germ line exon shuffling between unrelated genes.