THE NUCLEAR ENVELOPE IN DEVELOPMENT AND DISEASE

Basic Sciences

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Abstract

The vertebrate nuclear lamina is a protein meshwork associated with the nuclear face of the inner nuclear membrane (INM). It provides anchoring sites for chromatin domains, and is an important determinant of interphase nuclear architecture and DNA replication. The major components of the lamina are the intermediate filament-like proteins, the nuclear lamins, The lamins are grouped into 2 classes, A-type and B-type. The B-type lamins are encoded by 2 genes and are constitutively expressed whereas the A-type lamins are spliced variants from a single gene (Lmna) and their expression is developmentally regulated. To determine the function of the A-type lamins in embryogenesis we derived mice null for A type lamin expression. Development of the homozygotes to weaning appears normal. However all had perished by 8 weeks. The lamin null mice develop a form of muscular dystrophy, have little or no white fat and have abnormal hearts. Recently it has been shown that in humans different mutations in the Lamin A gene are responsible for at least 3 inherited forms of disease, the autosomal variant of Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy and Familial Partial Lipodystrohy. We are currently analyzing our mice to determine whether they exhibit all 3 disease states. We are also looking at what effects Lamin deficiency has on a cell's ability to replicate its DNA and segregate chromosomes at cell division. As the mice may also be lipodystrophic they may be of particular use in understanding how this condition arises in HIV infected patients who are being treated with the HIV protease inhibitor class of drugs.