title: Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb.
abstract: Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.
authors.affiliation: MRC Mammalian Genetics Unit, Harwell OX11 0RD, UK.
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Kurapati
authors.forename: Caoimhe
authors.initials: C
authors.lastname: McKenna
authors.forename: Johan
authors.initials: J
authors.lastname: Lindqvist
authors.forename: Debbie
authors.initials: D
authors.lastname: Williams
authors.forename: Michelle
authors.initials: M
authors.lastname: Simon
authors.forename: Emily
authors.initials: E
authors.lastname: LeProust
authors.forename: Jane
authors.initials: J
authors.lastname: Baker
authors.forename: Michael
authors.initials: M
authors.lastname: Cheeseman
authors.forename: Natalie
authors.initials: N
authors.lastname: Carroll
authors.forename: Paul
authors.initials: P
authors.lastname: Denny
authors.forename: Steve
authors.initials: S
authors.lastname: Laval
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Julien
authors.initials: J
authors.lastname: Ochala
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Blanco
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005808:Genes, Recessive; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009210:Myofibrils / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014158:Transcription, Genetic
chemical_list: C572750:MyHC IIb protein, mouse; D018995:Myosin Heavy Chains