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Ärende: Gene for Progeria discove
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Researchers Identify Gene for Premature Aging Disorder
Progeria Gene Discovery May Help Solve Mysteries of Normal Aging

WASHINGTON, D.C., April 16, 2003 - A team led by the National Human
Genome Research Institute today announced the discovery of the genetic
basis of a disorder that causes the most dramatic form of premature
aging, a finding that promises to shed new light on the rare disease, as
well as on normal human aging.

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 one 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 5 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 out 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.

"It's uncertain whether intelligence has any long term survival value.
Bacteria do quite well without it."

Stephen Hawking
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