Unraveling the Mysteries of Progeria

A young patient with Hutchison-Gilford progeria syndrome shows the physical signs of accelerated aging associated with this rare genetic disease.

A young patient with Hutchison-Gilford progeria syndrome shows the physical signs of accelerated aging associated with this rare genetic disease.

Hutchinson-Gilford progeria syndrome is a rare and devastating genetic disorder in which patients appear normal at birth, but by 12 to 18 months display signs of premature aging such as hair loss, slowed growth, weakening of bone and joint integrity, and cardiovascular disease. Because no treatments currently exist, most patients with progeria die in their mid-teens from heart disease or stroke.

In 2003 a mutation in the lamin A gene, resulting in an incompletely processed version of the protein, was identified as the cause of progeria. Lamin A is one member of a family of lamin proteins that regulate the structure of the nucleus, which houses a cell’s genetic information. It is unclear how mutations of this nuclear protein cause the physiological effects seen in progeria patients or why there is a delay of 12 months in the onset of the disease phenotype since lamin A is equally expressed before and after birth.

Lidia Hernandez working with Alan Perantoni, Ph.D. in the Cancer and Developmental Biology Laboratory, and Ira Daar, Ph.D. in the Laboratory of Cell and Developmental Signaling, in collaboration with Colin Stewart, Ph.D., a former NCI scientist who is currently at the Institute of Medical Biology in Singapore, and colleagues began to address these issues by studying their previously-generated mouse model of progeria, called Δ9, which also has a mutation in the lamin A gene, characterized by co-authors Kyle Roux, Ph.D. and Brian Burke, Ph.D. of the University of Florida. Though not identical to the human progeria lamin A mutation, the Δ9 mouse has similar physical abnormalities to progeria patients and serves as a good model to investigate the disease mechanism.

The researchers first investigated the processing and localization of the Δ9 mutated lamin A protein. Normally, lamin A is modified by the addition of a lipid group and then cleaved to remove the lipid and several residues from the end of the protein. Like the human progeria lamin A mutant, Δ9 retained its lipid group and was not properly cleaved. This incorrect processing did not, however, affect the targeting of Δ9 to the nuclear envelope, indicating that the progeria phenotype is likely not due to altered lamin A localization.

The scientists then looked for differences in the proliferation of cells derived from embryonic and two week old mice because one of progeria’s hallmarks is growth retardation that develops after birth. Cells derived from Δ9 embryos grew almost identically to wild type embryonic cells. Adult Δ9 cells, in contrast, detached from the substrate after only a few passages and died at twice the rate of adult wild type cells, mirroring the effects of mutated human lamin A. This increased cell death also correlated with a loss of smooth muscle cells in the blood vessels of adult Δ9 animals.

To determine what genes might be important in controlling the phenotype of the adult Δ9 cells, the researchers performed a microarray analysis comparing the expression of the Δ9 and wild type cells. The group of genes with the most significant changes encompassed extracellular matrix proteins, which are expressed on the cell surface and are important for cellular adhesion. Additionally, these genes are critical components of the mouse skeleton, and tests revealed reduced bone density and increased fragility in the Δ9 animals.

The scientists then wanted to determine whether changes in the extracellular matrix proteins were linked with the altered proliferation rates in the Δ9 cells. Surprisingly, normal growth was restored when adult Δ9 cells were plated onto extracellular matrix produced by wild type cells. This result suggests that mutation of lamin A in the nucleus alters the production of proteins at the cell surface which regulate cell proliferation and survival. Since these nuclear and extracellular proteins do not directly interact, the researchers searched for altered cell signaling pathways that might connect them. Three pathways showed reduced activity in adult Δ9 cells, but only one, the Wnt (pronounced went) pathway, was directly inhibited by Δ9 lamin A.

At least four of the altered genes from the adult Δ9 cell microarray are regulated by the Wnt pathway at the level of transcription. Lef-1 is a Wnt pathway transcription factor responsible for recruiting the transcription machinery to the promoter regions of genes it controls, and Lef-1 binding to these promoter regions was significantly reduced in adult Δ9 cells. The scientists demonstrated that this reduction in promoter association was due to a 90% decrease in Lef-1 protein levels. A similar reduction in Lef-1 protein levels was also found in two progeria patient cell lines. Interestingly, in wild type cells, Lef-1 protein is not produced until after birth suggesting that the loss of Lef-1-induced transcription may be the cause of the progeria phenotype and that its post-natal expression causes the disease’s delayed onset.

One well-known negative regulator of the Wnt pathway is GSK3β so the researchers tested whether a GSK3β inhibitor could rescue the adult Δ9 cells. Drug treatment stimulated the proliferation and survival of the mouse cells, and in fact, promoted proliferation in one of the human progeria cell lines. Using the Δ9 mouse model, Hernandez and colleagues demonstrated how changes in a structural protein in the nucleus can affect protein production at the cell surface via altered cellular signaling pathways. Future work will need to address how exactly mutated lamin A decreases Lef-1 protein levels and how knowledge of the role Wnt signaling plays in the disease process can lead to treatments for progeria patients.

Summary Posted: 09/2010


Dev. Cell. 2010 Sept 14; 10(3):413-425 PubMed Link