Download New Genetic Defect Identified in Some Cases of Inherited FTD

AFTD
The Association for Frontotemporal Dementias
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New Genetic Defect Identified in Some Cases of Inherited FTD
On July 16, 2006 in the scientific journal Nature two separate groups of researchers reported
new gene mutations that appear to be responsible for hereditary FTD in approximately 5% of
families with the disease. The gene involved is called PGRN, is located on chromosome 17,
and codes for the protein progranulin. This finding, although important, is relevant for
only a small number of FTD patients and their families with a clearly established,
inherited form of FTD. For the vast majority of cases of FTD the importance of these
new mutations is less clear. Nonetheless, the identification of this new genetic cause of
FTD in even a small group of cases is another important piece in the FTD puzzle, and
one that opens up new and important avenues of research.
The majority of patients (40%-75%) have a form of FTD that is sporadic—meaning that the
disease happened by chance in that individual, there is no family history of FTD, and there is
not a single major genetic cause. In this group there appears to be little, if any, risk of
recurrence in family members, and the current findings have no immediate impact.
In other families, based on the number of FTD and FTD-like diagnoses in the family, doctors
suspect that there is a genetic (inherited) component to the disease. Before these current
results were published, researchers had identified one specific gene responsible for a
significant proportion of hereditary FTD. This is the MAPT gene (also, by chance, located on
chromosome 17), which codes for the protein tau. Tau’s normal role in the brain is to
stabilize the neurons, which enables them to function normally. FTD patients with mutations
in the MAPT gene produce abnormal versions of the tau protein. The result is neurons that are
less stable than normal, and thus don’t function properly.
But only about 10% of FTD patients have a mutation in the MAPT gene, so scientists have
long suspected that there are other genes that can cause FTD. This is confirmed by these
current publications, which show that about 5% of FTD patients have a mutation in the
PGRN gene.
The PGRN gene contains instructions that tell cells how to make the protein progranulin.
Progranulin is a factor that stimulates cell growth and wound repair, although too much
progranulin has previously been linked to some cancers. Although the precise role of
progranulin in brain cells is unknown, FTD patients with PGRN mutations do not produce
enough functional progranulin. How this relates to the premature degeneration of nerve cells
in the frontotemporal region of the brain in FTD is unknown.
Identification of mutations in the PGRN gene as one cause of FTD is of immediate
importance only to families with a strong hereditary pattern of FTD related disorders, and
who are known to lack a mutation in the MAPT gene. If a PGRN mutation is found in these
families, almost certainly it would be the cause of the FTD for those individuals. At this
point, as there is no definitive therapy for any form of FTD, and the identification of the
mutation would be largely valuable for research purposes, although under special
circumstances members of an involved family may consider individual genetic testing.
This research is important because it demonstrates another mechanism that can cause nerve
cell degeneration in FTD. Once the precise mechanism by which reduced progranulin causes
disease has been identified, it may lead to promising new avenues for treatment. This is likely
to take many years, however.
Q&A
1. For families without a known family history of FTD, what is the importance of
this finding?
For families that do not exhibit a clear pattern of FTD being passed from generation
to generation, the identification of the PGRN gene has no immediate impact on care
or our understanding of the cause of FTD in your family. This applies to the majority
of FTD patients. It is important to consider consulting a genetic counselor familiar
with FTD and related disorders to help you understand whether your family has a
strong history of FTD that warrants additional testing.
FTD researchers nevertheless are very excited about this new information, as it is an
important step forward in our basic understanding of what can cause
neurodegeneration on the frontotemporal region of the brain (and thus cause FTD).
This research indicates that a functional PGRN gene (one that contains the
instructions for the neuron cell to make the growth factor progranulin) may be
necessary for the neuron to survive and work properly.
This is an important piece of information that suggests a new avenue for the
development of effective therapies: Researchers will now investigate the role of
progranulin in neuronal functioning and whether substances related to progranulin
might serve as the basis for future drugs to treat FTD.
2. What will the doctor do differently if a PGRN mutation is identified?
If a PGRN mutation is identified in an FTD patient, it means that the diagnosis of
FTD is confirmed (for the vast majority of FTD patients, the diagnosis cannot be
conclusively made until autopsy). It will also identify the specific cause of FTD in
that patient: an error (mutation) in the PGRN gene means that their brain cells cannot
produce enough functional progranulin, and without a sufficient amount of this
substance, neurons in the frontotemporal region of their brain are dying.
At this point there is no apparent impact on clinical care (just as there is none for
those with a defect on the MAPT gene that codes for tau).
Identification of a PGRN mutation would also have an impact on the patient’s
relatives. Just as with MAPT, if a specific mutation is identified, some family
members will be eligible for presymptomatic genetic testing. This means that a blood
test, analyzed in a laboratory that is certified to carry out this type of genetic study,
could tell them whether or not they inherited the same PGRN mutation, and thus
whether or not they themselves eventually will develop FTD. The decision to have
such testing requires careful consideration with a genetic counselor of all the possible
implications of knowing whether or not an individual is a gene carrier. This is
necessarily an involved process so that there is thorough understanding of the
ramifications of having this knowledge.
3. Could a PGRN mutation cause FTD, even if there is no family history?
It is possible. The age of disease onset in the PGRN cases varies considerably and can
occur at an older age (>70 yrs). This raises the possibility that previous members of
the family might have had the mutation, but died of other causes, before FTD would
have developed. Other possibilities include that a PGRN mutation may occur as a
new mistake in the patient, or that there may be a problem in the cell mechanism that
produces progranulin even if the genetic instructions are correct. These possibilities
are some of the next questions scientists will begin to address.
4. How do I know if a mutation in the PGRN gene is the cause of FTD in my
family?
The first step is to determine whether FTD is inherited in your family. We
recommend that you read the new AFTD publication "The Genetics of FTD: Should
You Worry?" to learn how to collect your family health history and to get a basic
understanding of genetics and genetic testing. (The booklet is available online or hard
copies can be ordered from the AFTD office for a nominal fee.)
The next step is to work with your physician and/or a genetic counselor. They will
compile all of the information and discuss whether or not genetic testing might be
informative for your family. (To find a genetic counselor who specializes in FTD
and/or other neurodegenerative diseases, contact your clinician or go to
www.nsgc.org)
5. Do mutations in the PGRN gene produce a specific subtype of FTD? Is there any
specific clinical symptom that would suggest that a PGRN mutation is
responsible?
There is a statistical tendency for individuals with a mutation of the PGRN gene to
have progressive aphasia. This is a disorder of language known to occur in FTD.
Conversely, tentative results from these early studies suggest patients with PGRN
mutations are much less likely to have motor neuron disease (ALS) than are FTD
patients without a mutation in this gene. These associations will have to be confirmed
by multiple studies before we can be sure they are not chance occurrences in the
patients studied thus far.
6. Have any differences been identified between FTD that is caused by mutations
in the MAPT gene vs. mutations in the PGRN gene?
Yes. The two genes code for two distinct proteins that each has their own function:
MAPT codes for tau, which provides structure to support the neuron, and PGRN
codes for progranulin, which may play a roll in cell growth and repair.
Scientists have known for many years that different proteins may accumulate
abnormally in the brain cells of FTD patients. One common cellular profile they see
is due to abnormal amounts or versions of the protein tau. A few years ago scientists
discovered that some of these cases were due to mutations in the gene that codes for
tau, the MAPT gene.
These new findings explain a second type of cellular pathology that scientists see in
some FTD patients. A mutation in PGRN is associated with the accumulation of
abnormal amounts of the protein ubiquitin in neurons. The connection between
ubiquitin and progranulin is not yet fully understood. Ubiquitin is usually attached to
other proteins—it is the cell’s way of marking damaged or misshaped proteins for
disposal. Scientists are currently trying to determine which proteins are attached to
ubiquitin in patients with this form of FTD, since it may help to reveal how mutations
in PGRN cause the disease.
7. Is it just coincidence that both the MAPT and PGRN genes are located near each
other on chromosome 17?
Our current understanding is that this is just a coincidence. The two genes code for
two distinct proteins with two different functions. They just happen to be located near
each other (like two different books that just happen to be on the same shelf). The
density of genes in this region of chromosome 17 is known to be one of the highest
observed in the entire human DNA sequence. This increases the possibility that
multiple genes linked to the same disease will be found close to another by chance
alone.
8. What next?
Even if the identification of the PGRN gene does not impact you or your family
today, we should all take encouragement from the fact that scientists around the
world are researching FTD, and making important strides in our understanding of this
disease.
It is always important to identify a genetic abnormality that is associated with a disease. This
adds another piece to solving the FTD puzzle. Hopefully it can point the way towards a
molecular basis for a treatment for this subtype of FTD, but we are likely many decades
away from that. It is important to remember that these results only apply to a subgroup of
familial patients and not to sporadic cases.
-- Jordan Grafman, Ph.D. NINDH , National Institutes of Health and member of the AFTD
Medical Advisory Council.
The finding of mutations in PGRN is incredibly important for our research. At last we know
what causes this genetic form of FTD and we can now start to determine the disease
mechanism, which is the first step to therapy. Although only around 5% of FTD patients
appear to have mutations in PGRN, a much larger proportion have the same
neuropathological changes in their brains. As a result, by understanding how PGRN
mutations cause FTD we are likely to have a much clearer idea of the disease mechanism in
this larger group of cases.
--Michael Hutton, PhD., Mayo Clinic, AFTD Medical Advisory Council
The results of these two studies open the door to valuable new avenues of research that
scientists will now pursue. The important work of Hutton, von Broeckhoven, and their
colleagues will lead to new diagnostic tests for identifying the cause of FTD in some patients.
It is important to keep in mind that these important new findings will have an immediate
impact only for a small number of individuals with FTD. With additional research funding
from NIH and other sources, scientists will be able to take advantage of these findings to
develop new therapeutic strategies for treating a large number of individuals with FTD.
--Murray Grossman, MD, PhD. Chair, AFTD Medical Advisory Council
Click here to see copies of the actual studies:
 Mayo Clinic Study
 von_Broeckhoven Study
Click here to see a copy of the July 17th announcement in Nature.com