Hutchison-Gilford Progeria Syndrome is a disease in which children experience very rapid aging. In all cases these children will experience rapid decay in their vascular, muscular, and skeletal systems until they die at about 15 years old usually from cardiovascular problems (stroke or heart attack). The Massachusetts Medical Society enrolled 15 children into this study ranging from ages 1 to 17 years of age, nearly half of the worlds known patients with this syndrome. The stereotypic phenotype we see from these individuals include sclerosis of the skin, joint contractures, bone abnormalities, alopecia (hair loss), and stunted growth. When studying the cardiovascular system they saw weakening heart function, high blood pressure, and hardening/thickening of the arterial walls. All of these problems are seen in normal human aging and if we can better understand the phenotypic malfunctions in Hutchinson-Gilford Progeria Syndrome then we may gain insight into normal human aging and bring us closer to finding ways to slow normal human aging.
The Medical Society also looked at this disease from a genetic standpoint. If you look at the LMNA gene's 12 exons you get two main splice products. Lamin C is encoded by exons 1 to 9 and a portion of exon 10. Lamin A results from alternative splicing which adds exons 11 & 12 and removes the Lamin C-specific portion of exon 10. It is during this splicing which the disease occurs. If LMNA gene is working properly the nuclear structure is maintained, transcription is regulated, there is proper differentiation of mesenchymal cells types (adipose and skeletal muscle tissues), and correct chromatin organization within the nucleus. In Hutchison-Gilford Progeria Syndrome there is a mutation in the LMNA gene where it encodes for Lamin A. At this particular location we see a change from glycine (GGC) to glycine (GGT). This causes an activation of cryptic splice site which leads to truncated proteins. This does not allow for proper nuclear structure (causes nuclear blebbing), disorganizes chromatin placement, and interrupts transcription. The next step in studying this disease is to see if this same malfunction in the LMNA gene occurs over a longer period of time in unaffected humans and if so, we can take steps to delay the onset of normal human aging.
New England Journal of Medicine, 2008, pgs. 592-604. www.nejm.org