title: Characterization of a novel ENU-generated myosin VI mutant mouse strain with congenital deafness and vestibular dysfunction.
abstract: Myosin VI (Myo6) is known to play an important role in the mammalian auditory and vestibular systems. We have identified a novel N-ethyl-N-nitrosourea mutagenised mouse strain, charlie, carrying an intronic Myo6 splice site mutation. This mutation (IVS5+5G > A) results in skipping of exon 5, and is predicted to cause a frameshift and premature termination of the protein. We detected essentially no Myo6 transcript in tissue from charlie homozygous mutant mice (Myo6(chl/chl)). Myo6(chl/chl) mice exhibit vestibular dysfunction and profound hearing impairment when first tested at four weeks of age. Analysis of vestibular and cochlear hair cells by scanning electron microscopy and immunohistochemistry revealed highly disorganised hair bundles with irregular orientation and kinocilium position at postnatal stage P2-P3. Within a few weeks, the majority of hair cell stereocilia are missing, or fused and elongated, and degeneration of the sensory epithelium occurs. This novel mouse strain will be an important resource in elucidating the role myosin VI plays in the mammalian auditory system, as well as its non-auditory functions.
authors.affiliation: Genetic Hearing Research Laboratory, Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Victoria 3052, Australia. louisehwilliams@gmail.com
authors.forename: Louise H
authors.initials: LH
authors.lastname: Williams
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Miller
authors.forename: Hans-Henrik M
authors.initials: HH
authors.lastname: Dahl
authors.forename: Shehnaaz S M
authors.initials: SS
authors.lastname: Manji
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001307:Auditory Perception; D001483:Base Sequence; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003051:Cochlea / Q000378:metabolism / Q000503:physiopathology / Q000648:ultrastructure; D003638:Deafness / Q000151:congenital* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D005038:Ethylnitrosourea / Q000494:pharmacology*; D020022:Genetic Predisposition to Disease; D006320:Hearing Tests; D006720:Homozygote; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008855:Microscopy, Electron, Scanning; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology*; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D014722:Vestibule, Labyrinth / Q000378:metabolism / Q000503:physiopathology* / Q000648:ultrastructure
chemical_list: D009153:Mutagens; C089785:myosin VI; D018995:Myosin Heavy Chains; D005038:Ethylnitrosourea