|Scientists Discover New Frontotemporal Dementia Gene
Scientists have discovered genetic mutations that cause a form of familial frontotemporal
dementia (FTD), a finding that provides clues to the underlying mechanism of
this devastating disease and that may provide insight for future approaches to
developing therapies. The mutations are contained in a single gene that scientists
can now identify as responsible for a large portion of inherited FTD. A rare
brain disorder, FTD usually affects people between ages 40 and 64 with symptoms
that include personality changes and inappropriate social behavior. Published
online July 16, 2006, in Nature, the research was funded by the National
Institute on Aging (NIA), part of the National Institutes of Health (NIH).
The discovery builds on a 1998 finding of mutations in another gene that is
responsible for a smaller proportion of inherited FTD cases. Amazingly, both
the gene found in 1998 and the newly found gene were found on the same region
of chromosome 17. Today’s discovery appears to explain all the remaining inherited
FTD cases linked to genes on chromosome 17 and may provide new insights into
the causes of the overall disease process. Geneticist Michael Hutton, Ph.D.,
of the Mayo Clinic College of Medicine, Jacksonville, Fla., led an international
scientific team to discover the new gene.
“This new finding is an important advance in our understanding of frontotemporal
dementia,” says NIA director Richard J. Hodes. “It identifies a mutation in the
gene producing a growth factor that helps neurons survive, and it suggests that
lack of this growth factor may be involved in this form of frontotemporal dementia.”
FTD encompasses a set of rare brain disorders. While most cases are sporadic,
an estimated 20 to 50 percent has a family history of dementia, according to
the Association for Frontotemporal Dementias. FTD affects the frontal and temporal
lobes of the brain. People with FTD may exhibit uninhibited and socially inappropriate
behavior, changes in personality and, in late stages, loss of memory, motor skills
and speech. There is no treatment.
Hutton and colleagues began looking for genetic causes of FTD after a 1996
NIA — funded conference on the disorder. The conference, he recalls, encouraged
researchers to cooperate, rather than compete, to find the FTD gene. At the start,
they knew only that the inherited changes were linked to chromosome 17. Two years
later, Hutton along with other researchers discovered that mutations in a particular
gene on chromosome 17 were responsible for a subset of inherited FTD cases. That
gene, called MAPT, contains instructions for a protein known as tau.
But, the researchers also knew there were many other families where FTD was
inherited but without mutations in the tau gene. Further searching of chromosome
17 in the families without tau mutations finally turned up what is reported today — another
set of mutations in another gene, this one containing instructions for the assembly
of a protein known as progranulin. The progranulin, or PGRN, gene, makes a growth
factor protein that stimulates cell division and motility during multiple processes
including embryonic development, wound repair and inflammation. Scientists say
it is unclear what role progranulin plays in the normal brain. In the FTD families,
they explain, the progranulin mutations appear to cut short the assembly process
for the protein in brain nerve cells (neurons), and the lack of progranulin eventually
causes neurons to die.
Understanding how the mutations of the two different genes on chromosome 17
cause neuronal death might help scientists better understand the different pathways
that cause dementia. The findings also suggest that PGRN may play a role in other
neurodegenerative diseases, such as ALS (Amyotrophic Lateral Sclerosis) or Lou
Gehrig’s disease, the researchers noted.
The study was conducted as part of the NIA-supported Alzheimer’s Disease Center
at the Mayo Medical Center. In addition to NIA funding, the researchers were
supported by several other entities in the United States, Belgium, Great Britain
and Canada, including, in the United States, the Mayo Foundation, the Robert
and Clarice Smith Fellowship program and the Alzheimer’s Association.
NIA leads the federal effort supporting and conducting research on aging
and the medical, social and behavioral issues of older people, including Alzheimer’s
disease and age-related cognitive decline. For information on dementia and
aging, please visit the NIA’s Alzheimer’s Disease Education and Referral (ADEAR)
Center at www.nia.nih.gov/alzheimers,
or call 1-800-438-4380. For more general information on research and aging,
go to www.nia.nih.gov.
The National Institutes of Health (NIH) — The Nation's Medical Research
Agency — includes 27 Institutes and Centers and is a component of
the U.S. Department of Health and Human Services. It is the primary federal
agency for conducting and supporting basic, clinical and translational medical
research, and it investigates the causes, treatments, and cures for both common
and rare diseases. For more information about NIH and its programs, visit www.nih.gov.