In 1994, the gene that is mutated in human X-linked EmeryDreifuss muscular dystrophy was found to encode a protein of the inner nuclear envelope named emerin. This link between the nuclear envelope and human disease was only the tip of an iceberg. Now genetic defects in nuclear envelope proteins are known to cause at least 14 disorders, including muscular dystrophies, lipodystrophies, and neuropathies. The most dramatic of these is Hutchinson-Gilford progeria. Affected individuals are essentially normal at birth, but they appear to age rapidly and die in their early teens of symptoms that are typically associated with extreme age.
Over 180 mutation scattered throughout the gene encoding both lamin A and c cause over 10 different diseases, collectively termed laminopathies. At least two laminopathies are also linked to mutations in FACE-I, the membrane-associated protease that processes prelamin A. Some of the symptoms of laminopathies can be modeled in the mouse. Loss of lamin A causes disruption of the nuclear envelope and leads to a type of muscular dystrophy. Other mutations in mouse lamin A reproduce aspects of Hutchin-son-Gilford progeria.
The most surprising aspect of the laminopathies is the fact that the defects are limited to a few tissues such as striated muscle, despite the fact that lamins A/C are ubiquitous in differentiated cells throughout the body. Lamin mutations appear to compromise the stability of the nuclear envelope, so it has been suggested that muscle nuclei might be particularly sensitive to these mutations, owing to mechanical stress during contraction. However, this mechanism cannot account for the link between lamin mutations and lipodys-trophy-fat is not a force-generating tissue- neuropathy, or progeria.
An alternative suggestion is that these mutations cause disease by altering gene expression by compromising interactions between the inner nuclear membrane and chromatin. Cells from patients with Hutchinson-Gilford progeria show signs of aging in culture that are accompanied by dramatic alterations in heterochromatin, lending support to this model.