Nuclear Lamin A Mutations in Progeria

2004 senior Scholar Award in aging

It has been thought for over 100 years that an understanding of the cause of an early onset premature aging disease called Hutchinson-Gilford Progeria Syndrome (HGPS), would provide insights into normal human aging. Progeria is an extremely rare disease that was recently found to be caused by several different mutations in the gene of a nuclear protein called lamin A. Infants with this disease typically appear normal at birth but begin to show abnormalities as early as 6 months of age. Early clinical indications are aged-looking skin, loss of subcutaneous fat, hair loss and short stature. As patients become older they often have hip dislocations, osteoporosis, abnormal development and premature loss of teeth, stiffness of the joints, and severe circulatory problems. Death at around 13 typically results from a heart attack or stroke. Furthermore, cultured cells derived from HGPS patients are prematurely senescent. Progeria is one of many diseases caused by mutations in human lamin A gene, collectively known as laminopathies. Many aspects of these diseases are related to aging phenomena such as bone loss, cardiac defects, diabetes and muscle atrophy. Interestingly, the reported mutations now number over 180 and they occur in different regions of the lamin A protein.

These findings are of great interest to us as a major focus of our research program has been to determine the structure and function of the nuclear lamins. The lamins are type V intermediate filament proteins that form the major component of the nuclear lamina, a fibrous meshwork located just beneath the nuclear envelope, where it forms a molecular interface between the inner nuclear envelope membrane and chromatin. Recently, we found that the lamins are also present throughout the nucleoplasm. Based upon this observation we have proposed that the lamins polymerize into higher order structures that form a complex ìnucleoskeleton.î We have hypothesized that this lamin-based nucleoskeleton forms an internal 3D network, coursing throughout the nucleus, interconnecting nuclear envelope components with chromatin and providing an internal scaffold, or platform, upon which macromolecules such as DNA and RNA are assembled.

We have found that the nuclei in cultured skin cells from HGPS patients appear normal initially. However, after continued growth in culture, they become progressively misshapen, highly lobulated and grossly disfigured. Intriguingly, during this process the nuclear lamina becomes extensively thickened and numerous other alterations in nuclear architecture occur, including an abnormal distribution of nuclear pores and a loss of heterochromatin, especially in the region of the nuclear lamina. Since HGPS patients are heterozygous with respect to this mutation, the mutant protein is expressed along with the wild type protein. Our preliminary morphological and biochemical results indicate that the progressive defects seen in the nuclei of these cells are due to the gradual accumulation of the abnormal lamin gene product.

Researchers
Robert D. Goldman Ph.D.
Northwestern University