In their study, to be released online next week in the journal Nature, researchers 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. There currently are no diagnostic tests or treatments for the progressive, fatal disorder.
Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute (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, the multi-institution research team included scientists from the Progeria Research Foundation, the New York State Institute for Basic Research in Developmental Disabilities in Staten Island, N.Y., the University of Michigan in Ann Arbor and Brown University in Providence, R.I.
W. Ted Brown, M.D., Ph.D., 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." Dr. Brown is widely regarded as the world's leading clinical expert on progeria.
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.
Leslie Gordon, M.D., Ph.D., medical director of the Progeria Research Foundation (PRF) and executive director of the PRF Genetics Consortium, said, "Isolating this gene is just the beginning. It is our goal to find treatments and possibly a cure for this rare, life-threatening disease that robs children of their adulthood. The Progeria Research Foundation will continue to lead the fight against progeria."
In 2001, PRF co-hosted a workshop with various institutes and centers of the National Institutes of Health (NIH), including the National Institute on Aging and the Office of Rare Diseases. The workshop brought together leading scientists from around the world to identify promising areas of research in progeria. This partnership eventually led to funding for progeria research and the formation of the PRF Genetics Consortium, a group of 20 scientists whose common goal is to find the genetic cause of progeria and to develop ways of treating the disease. Six of those scientists are co-authors of the study to be published in Nature.
Dr. Collins commended the collaborative efforts, saying, "The Progeria Research Foundation's commitment and cooperation played a key role in the hunt for the disease gene. They brought the urgent need to find this gene to the attention of the biomedical research community."
Earlier this week, Dr. Collins, as leader of the Human Genome Project, announced the successful completion of the international project's effort to sequence the 3 billion letters that make up the human genetic instruction book. "Free and unrestricted access to the human genome sequence is greatly speeding the pace of disease gene discovery. Finding the gene for progeria would have been impossible without the tools provided by the Human Genome Project," said Dr. Collins, who still spends some of his time in a small research lab at the National Institutes of Health (NIH). "This was a particularly challenging project for the gene hunters, since there are no families in whom the disease has recurred, and geneticists generally depend on such families to track the responsible gene. This was a detective story with very few clues."
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, Ph.D., 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.
To determine what effect abnormal lamin A has upon cells, the NHGRI-led team used fluorescent antibodies to track lamin A in skin cells taken from progeria patients known to have the common misspelling, as well as skin cells taken from unaffected people. The studies showed that about half of the cells from the progeria patients had misshapen nuclear membranes, compared with less than 1 percent of the cells from the unaffected controls.
"We suspect that this instability of the nuclear membrane may pose major problems for tissues subjected to intense physical stress - tissues such as those found in the cardiovascular and musculoskeletal systems, which are so severely affected in progeria," said Dr. Eriksson, noting that nuclear instability ultimately may lead to widespread death of cells.
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.
The new findings also may have implications for the treatment of progeria, with the newfound understanding of progeria's molecular roots pointing to possible therapeutic approaches. For example, researchers plan to explore the possibility that statins and/or other drugs known to inhibit a step in protein processing, known as farnesylation, might reduce the production of abnormal lamin A in progeria patients. Another avenue for identifying possible therapies involves screening large libraries of chemical molecules with the hope of finding a compound that can reverse the nuclear membrane irregularities seen in the cells of progeria patients.
"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."
Another interesting footnote to the recent findings is that different mutations in other regions of the LMNA gene previously have been shown to be responsible for a half-dozen other rare, genetic disorders. Those disorders are: Emery-Dreifuss muscular dystrophy type 2, limb girdle muscular dystrophy type 1B, Charcot-Marie-Tooth disorder type 2B1, the Dunnigan type of familial partial lipodystrophy, mandibuloacral dysplasia and a familial form of dilated cardiomyopathy.
Prior to coming to NIH to lead the Human Genome Project in 1993, Dr. Collins had established a reputation as a relentless gene hunter using an approach that he named "positional cloning." In contrast to previous methods for finding genes, positional cloning enabled scientists to identify disease genes without knowing in advance what the functional abnormality underlying the disease might be. Dr. Collins' lab, together with collaborators, applied the new approach in 1989 in their successful quest for the long-sought gene responsible for cystic fibrosis. Other major discoveries soon followed, including identification of the genes for neurofibromatosis, Huntington's disease, multiple endocrine neoplasia type 1, one type of adult acute leukemia and Alagille syndrome.
NHGRI is one of the 27 institutes and centers at the NIH, which is an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its Web site: www.genome.gov.