Muscular laminopathies: Role of prelamin A in early steps of muscle differentiation.

Mutations in A-type lamins or lamin-binding proteins are involved in the pathogenesis of diseases referred to as laminopathies (Worman et al., 2009). They include both tissue-specific disorders affecting striated muscle (muscular laminopathies), adipose tissue (lipodystrophic laminopathies), and syndromes in which many tissues undergo premature ageing (progeric laminopathies). Howmutations in LMNA cause diverse diseases is one of the most intriguing riddle in medical genetics. Two hypotheses have emerged to account for the molecular basis of the wide spectrum of these diseases. The mechanical stress hypothesis, mainly based on observations in cultured cells, proposes that mutations in A-type lamins lead to increased nuclear fragility and eventual nuclear disruption in tissues exposed to mechanical strain (Lammerding et al., 2005). The gene expression hypothesis suggests that mutations in A-type lamins lead to abnormal tissue-specific gene regulation. This model is based on findings that A-type lamins and associated proteins bind to chromatin and transcriptional regulators. The gene expression hypothesis does not exclude effects that mechanical stress may have on cells; in fact, both gene expression, as well as signalling pathways and mechanical integrity should be perturbed in cells carrying laminopathy mutations (Cohen et al., 2008). Furthermore, signalling pathways that culminate in transcription factor activity may also be regulated at the nuclear envelope and lamina, which act as a platform or scaffold necessary for the appropriate localization of factors important in specific tissue differentiation (Schirmer and Foisner, 2007; Pekovic and Hutchison, 2008; Andrés and Gonzalez, 2009).