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

Hum Mol Genet. 2000 Mar 22;9(5):821-8. doi: 10.1093/hmg/9.5.821.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Brain / cytology
  • Brain / metabolism*
  • DNA, Complementary
  • Exons*
  • Fungal Proteins / genetics*
  • GTP-Binding Protein beta Subunits*
  • Gene Dosage
  • Genes, Recessive
  • Introns
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microscopy, Electron
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / genetics*
  • Myosin Type I*
  • Myosins / genetics*
  • Purkinje Cells / metabolism
  • Purkinje Cells / ultrastructure
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Saccharomyces cerevisiae Proteins*


  • DNA, Complementary
  • Fungal Proteins
  • GTP-Binding Protein beta Subunits
  • Gnb5 protein, mouse
  • MYO5 protein, S cerevisiae
  • RNA, Messenger
  • Saccharomyces cerevisiae Proteins
  • Myosin Type I
  • Myosins
  • Monomeric GTP-Binding Proteins