Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb

Ramakrishna Kurapati, Caoimhe McKenna, Johan Lindqvist, Debbie Williams, Michelle Simon, Emily LeProust, Jane Baker, Michael Cheeseman, Natalie Carroll, Paul Denny, Steve Laval, Hanns Lochmueller, Julien Ochala, Gonzalo Blanco*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1706-1724
Number of pages19
JournalHuman Molecular Genetics
Volume21
Issue number8
DOIs
Publication statusPublished - 15 Apr 2012

Keywords

  • ACTIN
  • MUSCLE
  • AUTOSOMAL-DOMINANT MYOPATHY
  • MICE
  • BOUND NUCLEOTIDE
  • MYOSIN HEAVY-CHAIN
  • HYALINE BODY MYOPATHY
  • HYPERTROPHIC CARDIOMYOPATHY
  • STORAGE MYOPATHY
  • MISSENSE MUTATION

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