The discovery that mutations in myosin and actin genes, together with mutations in the
other components of the muscle sarcomere, are responsible for a range of inherited muscle diseases
(myopathies) has revolutionized the study of muscle, converting it from a subject of basic science to a
relevant subject for clinical study and has been responsible for a great increase of interest in muscle
studies. Myopathies are linked to mutations in five of the myosin heavy chain genes, three of the
myosin light chain genes, and three of the actin genes. This review aims to determine to what extent
we can explain disease phenotype from the mutant genotype. To optimise our chances of finding the
right mechanism we must study a myopathy where there are a large number of different mutations
that cause a common phenotype and so are likely to have a common mechanism: a corollary to
this criterion is that if any mutation causes the disease phenotype but does not correspond to the
proposed mechanism, then the whole mechanism is suspect. Using these criteria, we consider two
cases where plausible genotype-phenotype mechanisms have been proposed: the actin “A-triad” and
the myosin “mesa/IHD” models.