The discovery of the genetic basis of a disorder that causes the most dramatic form of premature aging promises to shed new light on the rare disease, as well as on normal human aging.

Led by the National Human Genome Research Institute (NHGRI), the research team included Michael Boehnke, Laura Scott, and Joel Singer of the University of Michigan School of Public Health Department of Biostatistics and the UM Center for Statistical Genetics.

The study, published in the journal Nature, identified the genetic mutations responsible for Hutchinson-Gilford progeria syndrome (HGPS), commonly referred to as progeria. Derived from the Greek word for old age, “geras,” progeria is estimated to affect 1 in 8 million newborns worldwide, according to the NHGRI. There currently are no diagnostic tests or treatments for the progressive, fatal disorder.

Francis S. Collins, director of the NHGRI and leader of the research team, said, “This genetic discovery represents the first piece in solving the tragic puzzle of progeria. Without such information, we in the medical community were at loss about where to focus our efforts to help these children and their families. Now, we finally know where to begin.”

Dr. Collins added, “The implications of our work may extend far beyond progeria – to each and every human being. What we learn about the molecular basis of this model of premature aging may provide us with a better understanding of what occurs in the body as we all grow older.”

In addition to NHGRI and the University of Michigan, the multi-institution research team included scientists from the Progeria Research Foundation, the New York State Institute for Basic Research in Development Disabilities in Staten Island, N.Y., and Brown University in Providence, R.I.

W. Ted Brown, co-author of the study and chairman of the Department of Human Genetics at the Institute for Basic Research, said, “Many people consider progeria to be the most dramatic example of a genetic disease that clearly resembles accelerated aging. The children appear to have an aging rate that is five to 10 times what is normal.”

According to the NHGRI, children with progeria usually appear normal at birth. However, within a year, their growth rate slows and their appearance begins to change. Affected children typically become bald with aged-looking skin and pinched noses. They often suffer from symptoms typically seen in elderly people, especially severe cardiovascular disease. Death occurs on average at age 13, usually from heart attack or stroke.

Taking advantage of an array of genomic technologies – from whole-genome scans to high-throughput sequencing of targeted DNA regions – researchers determined the most common cause of progeria is a single-letter “misspelling” in a gene on chromosome 1 that codes for lamin A, a protein that is a key component of the membrane surrounding the cell’s nucleus. Specifically, the researchers found that 18 of 20 children with classic progeria harbored exactly the same misspelling in the lamin A (LMNA) gene, a substitution of just a single DNA base – a change from cytosine (C) to thymine (T) – among the gene’s 25,000 base pairs. In addition, one of the remaining progeria patients had a different single base substitution – guanine (G) to adenine (A) – just two bases upstream. In every instance, the parents were found to be normal indicating that the misspelling was a new, or “de novo,” mutation in the child.

At first glance, the point substitution in the LMNA gene would appear to have no effect on the production of lamin A protein. “Initially, we could hardly believe that such a small substitution was the culprit. How could these bland-looking mutations lead to such terrible consequences in the body?” said NHGRI’s Maria Eriksson, a post-doctoral fellow in Dr. Collins’ lab and the first author of the study.

However, when Dr. Eriksson conducted laboratory tests on cells from progeria patients, she found that the minute change in the LMNA gene’s DNA sequence dramatically changed the way in which the sequence was spliced by the cell’s protein-making machinery. The end result was the production of an abnormal lamin A protein that is missing a stretch of 50 amino acids near one of its ends.

"The rapid identification of a variant in lamin A as the basis for progeria demonstrates the value of the new tools provided by human genome sequencing and annotation and the importance of a strong interdisciplinary team of clinical, molecular, and statistical geneticists," explained Michael Boehnke, professor of Biostatistics at the University of Michigan and a member of the research team.

Researchers hope to move their new findings into the clinic almost immediately with the development of a genetic test for progeria. Such a test will help doctors diagnose or rule out progeria in young children much earlier than their current method of looking at outward physical changes, according to the NHGRI.

“It is impossible to predict how soon our findings will translate into treatments for children suffering from progeria. We and other researchers across the nation will be working hard to find ways of helping them. Unfortunately, as we have witnessed with other genetic discoveries, the road from the lab to the clinic is not always swift or smooth,” Dr. Collins said.

More also remains to be done to determine what role the LMNA gene may play in the normal aging process. “Aging clearly has a strong genetic component. Discovery of this key genetic mutation that causes progeria may lead to a much clearer understanding of what causes aging in us all. Eventually, this information may lead to improvements in health care for our aging population,” said Dr. Brown.

Researchers plan to look at the LMNA genes of people who are exceptionally long-lived to see if there are any variants of the gene associated with longevity. Other studies might focus on determining whether repeated damage to the LMNA gene over the course of a lifetime may influence the rates at which people age.

“Our hypothesis is that LMNA may help us solve some of the great mysteries of aging,” Dr. Collins said. “However, it will probably take more than one genetic key to unlock the secrets to a biological process as complex as aging. There are probably a host of other genes related to aging still waiting to be discovered.”

Contact: Terri Mellow, Director, SPH Office of Communications
Phone: (734) 764-8094
E-mail: twm@umich.edu

© 2003 The Regents of the University of Michigan
Updated April 28, 2003