Chapter 17. Mutations in the Mouse LMNA Gene Causing Progeria, Muscular Dystrophy and Cardiomyopathy

Summary

At least ten different diseases have been linked to mutations in proteins associated with the nuclear envelope (NE). Eight of these diseases are associated with mutations in the lamin A gene (LMNA). These diseases include the premature ageing or progeric diseases Hutchinson-Gilford progeria and atypical Werner's syndrome, diseases affecting striated and cardiac muscle including muscular dystrophies and dilated cardiomyopathies, lipodystrophies affecting white fat deposition and skeletal development and a peripheral neuropathy resulting in motor neuron demyelination. To understand how these diseases arise from different mutations in the same protein, we established mouse lines carrying some of the same mutations found in the human LMNA gene, as both mouse and human lamin genes show a very high degree of sequence conservation. We have generated mice with different mutations resulting in progeria, muscular dystrophy and dilated cardiomyopathy. Our mouse lines are providing novel insights into how changes to the nuclear lamina affect the mechanical integrity of the nucleus and in turn intracellular signalling, such as the NF-κB pathway, as well as cell proliferation and survival, cellular functions that, when disrupted, may be the basis for the origin of such diseases.