Abstract for presentation at 11th International Congress of Human Genetics

Novel slow-skeletal/beta cardiac myosin mutations in Laing early onset distal myopathy and myosin storage myopathy

  • Danielle Dye, University of Western Australia, Australia
  • Kendall Walker, University of Western Australia, Australia
  • Bjarne Udd, Folkhalsan Institute of Genetics, Finland
  • Kathy Wagner, Johns Hopkins Hospital, United States
  • Alex Barboi, Medical College of Wisconsin, United States
  • Hans Goebel, Johannes Gutenberg University, Germany
  • Nigel Laing, University of Western Australia, Australia

    • Mutations in the slow-skeletal/beta-cardiac myosin gene (MYH7) have been implicated in hypertrophic and dilated cardiomyopathy, Laing early-onset distal myopathy and myosin storage myopathy.
    Purpose: To identify the genetic basis of further patients presenting with clinical and/or histopathological features similar to Laing myopathy and myosin storage myopathy. Methods: Patient DNA was amplified for MYH7 exons 30-40 and analysed by direct sequencing. Control DNA was screened for identified mutations by sequencing, single strand conformation polymorphism analysis (SSCP) or restriction enzyme digestion. COILS analysis was used to investigate the effect of the amino-acid changes on predicted protein structure. Results: Laing myopathy: we identified three novel heterozygous mutations (c.L1646P, c.R1662P, c.K1729insK) and three further families with the published c.K1617del mutation. Myosin storage myopathy: one novel mutation, c.L1793P. These mutations are clustered in the region of MYH7 coding for the light meromyosin region of the myosin tail and were not seen in >100 control chromosomes. Laing myopathy mutations involve either a lysine insertion/deletion or a proline substitution and disrupt the ability of the myosin tail to form a coiled-coil (its normal structure). The myosin storage myopathy mutations involve a range of substitutions and show heterogeneity in their ability to disrupt the coiled-coil. Conclusions: Mutations in the LMM region of MYH7 are known, at present, to cause 4 distinct clinical entities – hypertrophic and dilated cardiomyopathies, Laing myopathy and myosin storage myopathy. Whilst the mutations associated with Laing myopathy are quite specific, those associated with the other diseases are more diverse and vary in their effect on the coiled-coil structure. How adjacent mutations in the LMM region of MYH7 lead to at least 4 distinct disease phenotypes remains to be elucidated.

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