When lamins go bad: nuclear structure and disease

Abstract

Mutations in nuclear lamins or other proteins of the nuclear envelope are the root cause of a group of phenotypically diverse genetic disorders known as laminopathies, which have symptoms that range from muscular dystrophy to neuropathy to premature aging syndromes. Although precise disease mechanisms remain unclear, there has been substantial progress in our understanding of not only laminopathies, but also the biological roles of nuclear structure. Nuclear envelope dysfunction is associated with altered nuclear activity, impaired structural dynamics, and aberrant cell signaling. Building on these findings, small molecules are being discovered that may become effective therapeutic agents.

Figure 1. Signaling pathways disrupted by LMNA mutations

Recent years have seen several discoveries of signal transduction pathways that are altered in LMNA mutant backgrounds associated with gain-of-function toxicity, loss-of-function or both. A list of pathways are provided that are described in detail in the text.

Figure 2. Potential therapeutic approaches to laminopathies

Several small molecules have been proposed as treatments for laminopathies. The major ones are listed with arrows indicating the diseases to which they may have efficacy. Question marks indicate that animal data has yet to be presented. Notably, FTIs have been tested in human children with HGPS with promising initial results (Gordon et al., 2012).