Identification of a novel myosin-Va mutation in an ataxic mutant rat, dilute-opisthotonus

. Mutations of the myosin-Va gene ( Myo5a ) cause diluted coat color in mice and are occasionally associated with severe neurological disorders. Dilute-opisthotonus ( dop ) is a spontaneous gene mutation in the rat, and phenotypes of the homozygote ( dop/dop ) are similar to those of the Myo5a- deficient mouse, suggesting that the mutation resides in the rat Myo5a gene. To elucidate the molecular basis of the dop mutation, we cloned the rat Myo5a cDNA from the wild type and the dop/dop. The wild-type rat Myo5a cDNA contained a 5487-bp ORF and showed higher homology with Myo5a of the other species than Myr6 ( Myo5b ) in the rat. A 141-bp in-frame deletion was detected in the head region in the dop cDNA. An intragenic rearrangement consisting of a 306-bp inversion associated with 17-bp and 217-bp deletions were identified in the Myo5a gene of the dop genome. This rearrangement involved a 141-bp exon, which was skipped in the dop transcript. The MyoVA protein expression was severely impaired in the dop/dop brain. This is the first report to define the dop mutation as the Myo5a gene abnormality in the rat.