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 behaviour. 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, Florida, 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 behaviour, 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.