title: The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a.
abstract: 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.
authors.affiliation: Department of Human Genetics, 4708 Medical Science II, University of Michigan, Ann Arbor, MI 48109-0618, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Jones
authors.forename: J D
authors.initials: JD
authors.lastname: Huang
authors.forename: V
authors.initials: V
authors.lastname: Mermall
authors.forename: B A
authors.initials: BA
authors.lastname: Hamilton
authors.forename: M S
authors.initials: MS
authors.lastname: Mooseker
authors.forename: A
authors.initials: A
authors.lastname: Escayg
authors.forename: N G
authors.initials: NG
authors.lastname: Copeland
authors.forename: N A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: M H
authors.initials: MH
authors.lastname: Meisler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D018076:DNA, Complementary; D005091:Exons; D005656:Fungal Proteins / Q000235:genetics*; D044387:GTP-Binding Protein beta Subunits; D018628:Gene Dosage; D005808:Genes, Recessive; D007438:Introns; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D024461:Myosin Type I; D009218:Myosins / Q000235:genetics*; D011689:Purkinje Cells / Q000378:metabolism / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins
chemical_list: D018076:DNA, Complementary; D005656:Fungal Proteins; D044387:GTP-Binding Protein beta Subunits; C094668:Gnb5 protein, mouse; C100412:MYO5 protein, S cerevisiae; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D024461:Myosin Type I; D009218:Myosins; D020559:Monomeric GTP-Binding Proteins