New Genetic Mutation Identified:
Most Common Cause of FTD and ALS,
Accounting for as Much as One Third of All Familial ALS
Two independent studies, both funded by The ALS Association,
have found a genetic abnormality that, according to researchers, is the most
common cause of Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia
(FTD). As reported in the recent online issue of the scientific journal Neuron,
an unusual mutation was discovered, where a short DNA sequence is repeated many
more times as compared to healthy individuals.
Using next generation sequencing
in a study led by Bryan J. Traynor, M.D., Laboratory of Neurogenetics, National
Institute on Aging, the team identified a GGGGCC hexanucleotide repeat within
the non-coding region of a gene on chromosome 9p21. This repeat accounts
for nearly 50% of familial ALS cases in Finland and more than a third of
familial cases in other European populations.
The identification of the same
genetic abnormality was independently made by a group at Mayo Clinic in
Jacksonville, Florida led by Rosa Rademakers, Ph.D. and published in the same
journal. The repeat of C and G (two of the four nucleotides that make up
the genetic code) was found in a non-coding region of a gene called C9ORF72,
which has no known function and its role in disease remains a mystery.
“We believe that when the
defective gene is transcribed into a messenger RNA molecule, the expanded
repeat section causes the RNA to bind tightly to certain proteins, forming
clumps within the brain cells,” according to Dr. Rademakers. “By binding
these proteins, the abnormal RNA may prevent these proteins from carrying out
their normal functions in the cell.”
The identification of the genetic lesion on the chromosome
9p21 locus marks a major milestone in ALS research. Several studies have
led to the identification of this region linked to chromosome 9p21 including
recent genome-wide association (GWA) studies (visit http://www.alsa.org/news/archive/genome-study-identifies-link.html
to read a report).
Investigators worldwide have been committed to identifying
the gene alteration, and until now it had remained elusive. This
hexanucleotide repeat was identified using state of the art next-generation
sequencing technology. “The repeat expansion was highly associated with
ALS and FTD in the Finnish population,” said Dr. Traynor.
“Since all routine methods of genetic analysis had failed to
find the genetic defect in this region, we suspected the defect could be a rare
DNA repeat expansion,” said lead investigator Mariely DeJesus-Hernandez from
the Mayo Clinic-led research team. This team found an area of DNA that in
healthy individuals is normally repeated only 2 to 23 times, but in ALS or FTD
patients is repeated 700-1,600 times. These changes were found in almost
12 percent of familial FTD and more than 23 percent of familial ALS samples
studied at Mayo Clinic.
The defect is also the strongest genetic risk factor found
to date for the more common, non-inherited, sporadic forms of these diseases.
It was found in 3 percent of sporadic FTD and 4 percent of sporadic ALS
samples in Mayo Clinic’s large clinical patient series.
“This finding has the potential to lead to significant
insights into how both of these neurodegenerative diseases develop, and may
give us much needed leads into new ways to treat our patients,” said Senior
Investigator Rosa Rademakers, a neuroscientist at the Mayo Clinic campus in
The repeat expansion is more than twice as common as the SOD1
gene in familial ALS and four times as common as TDP43, FUS, VCP
combined. The identification of this repeat and the rapid, reliable
method of screening individuals for repeat expansion may have immediate utility
by allowing early identification of ALS patients at risk of cognitive
impairment and FTD cases at risk of progressive paralysis.
In the long term, the identification of the genetic lesions
underlying the chromosome 9p21 ALS-FTD together with the high frequency makes
it an ideal target for drug development aimed at ameliorating the disease
process. “Whether the pathogenic process is linked to a loss of function
in which the expansion disrupts splicing of the target or through the
generation of toxic RNA disrupting normal cellular processes will be determined
by further study,” added Traynor. “However the large size of the
expansion and its location in a non-coding region may argue for the later
Disruption of RNA metabolism has already been identified as
an important mechanism in those cases with TDP43 and FUS mutations, and this
discovery provides further evidence for disrupted RNA metabolism as a key
underlying cause of disease.
“This is tremendously exciting,” commented ALS Association
Chief Scientist Dr. Lucie Bruijn, Ph.D. “These findings will
significantly impact the field as we begin to understand more about the
consequence of these changes to the disease process, aid our understanding of
FTD and ALS, potentially provide a diagnostic tool, and enable the development
of new therapeutic approaches.
Dr Traynor’s team was funded by The ALS Association’s
Abendroth ALS Genetic Discovery Fund, with additional funding from the Robert
Packard Institute of ALS Research at Johns Hopkins. Dr. Rademakers’ team
was funded by the The ALS Association’s Florida Chapter and Richard Essey, founder of the Greater Bay Area Chapter.
Both studies were funded by the National Institute on Aging and the
National Institute on Neurological Diseases and Stroke