How does genotype define phenotype? Microphysiology of a tropomyosin mutation in situ shows the limitations of reductionism.

摘要

Tropomyosin is one of the components of muscle thin filaments. In concert with the troponin complex it forms the regulatory Ca~(2+) switch of striated muscles. The tropomyosin molecule is a parallel coiled-coil dimer of 274 amino acids which is almost 100% a-helix. Two strands of tropomyosin molecules joined end-to-end are wound around the actin double helix to form the core of the thin filament. Traditionally tropomyosin has been regarded as a passive player in muscle regulation, whose function is merely to transmit Ca~(2+) activation signals from troponin along the filament. However, in recent years tropomyosin mutations have been found to cause a number of clinically significant myopathies including hypertrophic cardiomyopathy, dilated cardiomyopathy,distal arthrogryposis, nemaline myopathy and congenital fibre-type disproportion. In the same way that disease-causing mutations in myosin heavy chain, myo-sin binding protein C and troponin T have sparked off renewed investigations of apparently well-known proteins, the discovery of mutations in tropomyosin has stimulated many new structural and biochemical studies of phenotype-genotype relationships. The emerging story is that tropomyosin is a much more interesting molecule than previously thought and it plays a very fundamental role in muscle regulation. From structural investigations it is now evident that tropomyosin is not a pure coiled-coil cu-helix (Brown et al. 2001).