Mayo Magazine

A World of Possibilities
Discovery of a Mutation Opens the Door to Dementia Research

Maybe we'll find it today; maybe we'll find it tomorrow; or maybe we'll never find it. Those thoughts were all at the back of Jennifer Gass' mind when she started her day on April 7, 2006. A research technician at Mayo Clinic Jacksonville, she was in the midst of an exciting project: the search to find the gene responsible for an inherited form of frontotemporal dementia (FTD), which researchers had observed in several North American and European families.

She knew that discovering the gene would be an extraordinary find, one that would be relevant to the many patients around the world with FTD. For that reason, teams in several countries were racing to make the discovery.

But the search had become the proverbial needle in a haystack. Ms. Gass works in the research lab of Michael Hutton, Ph.D., and she had been looking for the gene for more than a year. Her work focused on studying 160 genes located on chromosome 17. And she was a relative newcomer to the project. Matt Baker, a senior research technologist in Dr. Hutton's lab; Bradley Boeve, M.D., a neurologist at Mayo Clinic Rochester; and Dr. Hutton had been searching for 10 years.

For this group, and for Rosa Rademakers, Ph.D., a visiting scientist who joined Dr. Hutton's lab in early 2006, the line between success and continued frustration turned out to be thin and red. A line with those features drew Ms. Gass' attention as she scanned the results of a DNA-sequence test for a little-known gene that produces progranulin, a protein that has previously been studied only by cancer researchers.

The sequence test analyzed DNA samples from seven patients with FTD and compared the results to samples from a small group of people without the dementia. The test generated a report that graphed each DNA sample, using colored lines that formed peaks corresponding to each person's DNA. And in one of the patient samples, two peaks overlapped: a blue peak, which was consistent with the reports for healthy people, and a smaller red peak, which was not consistent.

It was something that Ms. Gass had never seen before, but it was not, at first glance, proof of a mutation or disease causation. More tests would have to be done to prove if either of those possibilities was true.

A knockout gene
Over the next few days Dr. Hutton's team would discover that the patient samples had a mutated progranulin gene, a shortened version of the gene, missing about four pair of nucleotides — the individual components of DNA, which strand together in pairs. Checking other patient samples, the team soon found similar mutations at various points along the gene's code. No such changes were observed in samples from healthy people.

Further testing revealed that the mutations affected the gene's functioning. Ultimately, the team identified 23 different mutations in progranulin, and each one had the same effect. The mutations effectively knocked out one copy of the gene. As a rule, people have two copies of each gene, which they inherit from their parents, so the mutations caused a 50 percent drop in the production of progranulin.

The team shared the news with a collaborator in Belgium, Christine Van Broeckhoven, Ph.D., and she discovered similar results in patient samples that she had. It was time to celebrate, says Mr. Baker.

"Discovering that the mutation was in another family and was linked to the disease was the final thing," Mr. Baker says.

Meanwhile, in Manchester ...
An ocean away, Stuart Pickering-Brown, Ph.D., also had reason to celebrate. An associate professor at the University of Manchester, in the United Kingdom, Dr. Pickering-Brown spent two years in Dr. Hutton's lab searching for the gene that Ms. Gass eventually found. Though he didn't discover the gene, he helped lay the groundwork for its discovery, thanks to help from a Mayo benefactor.

Funds from a fellowship program established by Robert and Clarice Smith allowed Dr. Pickering-Brown to identify a large family in British Columbia with an extensive history of FTD. Analyzing DNA from this family, Dr. Pickering-Brown established two pieces of information that helped make the progranulin discovery possible.

First, he showed that the family members didn't have any mutations in the tau gene, which previous research had identified as a cause of FTD. That helped other scientists embrace the idea that there could be more than one genetic cause for the disorder.

Secondly, Dr. Pickering-Brown's research helped narrow the search for the gene later discovered by Ms. Gass. Through various screening techniques, genetics researchers can compare DNA between family members who have a disease and those who are unaffected, to establish a general location for a disease-causing mutation. Dr. Pickering-Brown's data yielded the 160-gene area that contained progranulin.

"I don't think we would have found the progranulin mutations without the Smith Fellowship and the samples from this Canadian family," says Dr. Pickering-Brown, who is listed as a joint first author on the paper in Nature that announced the progranulin discovery.

Indeed, the progranulin experience is a textbook example of why philanthropy is necessary for medical research, says Dr. Boeve.

"To find answers, we need to look down a bunch of avenues, and maybe only one in 10 of those avenues will turn up something; that's just how medical research works," he says. "But we have fantastic investigators and scientists and the infrastructure in the Birdsall Building (in Jacksonville) is fabulous. What it comes down to is funding, and to do this type of high-risk, high-reward work, we need philanthropy."

A promising enigma
The progranulin finding is only an end to a beginning, and a surprising one at that. Prior to the discovery, no one had been studying progranulin's role in brain functioning. And the mutation's effects — a reduction in protein production — are also unusual because usually these changes cause genes to take on extra functions, not limit them, says Dr. Rademakers, who has published research showing that 5 percent of FTD patients worldwide have progranulin mutations.

But the mutation's effect may turn out to be an advantage from a treatment perspective, says Dr. Boeve, because it suggests therapy may not be far away. It may be possible to treat people who have progranulin mutations by using drugs that stimulate the production of progranulin, he says, and several drugs may be able to do that.

"We don't know why loss of progranulin causes people to develop a neurological disorder with symptoms that become evident between the ages of 50 and 70," Dr. Boeve says. "But at the same time, we may have an easier time developing therapies for FTD associated with progranulin mutations, in comparison to diseases like Alzheimer's or Parkinson's, which we know much more about."

Still, even this possibility only begins to describe the potential that studies of progranulin may have for FTD and other neurological disorders. Although the mutation is present in a relatively small number of patients, it leads to a brain pathology that is commonly seen in people with FTD. People with the mutations, and about 50 percent of all patients with FTD, have abnormal clumps of a protein called TDP-43 in their brains. These protein clumps are linked to the cell dysfunction and cell death that occurs in FTD.

"Not only do we now understand the cause of FTD in the rare individuals that have the mutations," says Dr. Hutton, "we now know one process by which this disease is caused in a large group of FTD patients."

Priming the progranulin pump
And there's more. The same protein, TDP-43, that clumps in the brains of people with FTD also clumps in the brains of people with amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, but in a different part of the brain. Perhaps loss of progranulin has something to do with ALS as well. And Dr. Hutton says there's also evidence suggesting that progranulin may be relevant to Alzheimer's studies.

"We don't have the resources to investigate all of these possibilities," he says. "But these findings point to a fundamental question: What is progranulin's function in normal brain cell activity? We have to find out. The idea is to translate our genetic studies in order to mimic this form of FTD in animals and then to use that information to identify safe, effective therapies for patients."

Dr. Hutton is quite familiar with the path he describes. He and colleagues in the Neurosciences Department have used a similar blueprint to identify new treatments for other forms of FTD, as well as new possibilities for treating Alzheimer's disease. The Alzheimer's drug, identified by Todd Golde, M.D., is now in Phase II clinical trials, and FTD therapies are only a few years from the first phase of clinical tests.

In addition to working on therapeutics, Dr. Hutton and colleagues are already searching for another important gene related to FTD. Working again with patients and families from across the globe, they have traced their genetic suspect to a region on chromosome 9. It's particularly important because the mutation causes patients to develop both FTD and ALS, and it leads to the same pathology seen in FTD patients with progranulin mutations.

"When that gene is discovered, we'll have a huge part of the puzzle," Dr. Hutton says. "We'll have two genetic causes for that type of FTD, and we'll know the protein that accumulates in the brain. I know that gene will be found within the next year. Maybe not by us, but I know somebody is going to find it."

The thrill of discovery

She doesn't call herself an explorer, a pioneer or any other grandiose term, but Jennifer Gass has witnessed some amazing phenomena, all the same.

A research technician in the lab of Michael Hutton, Ph.D., at Mayo Clinic Jacksonville, Ms. Gass made a discovery that most people in her field will never make. She identified a disease-causing genetic mutation for frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease and Lewy body disease. These types of genes — and their discovery — are universally rare.

But, reflecting on the discovery, Ms. Gass says its rarity was only one of her initial thoughts. "For the first few minutes, my lab partners and I were the only ones in the world who knew that this gene was a cause of FTD," she says.

A great start
And it was a precursor of things to come, because in the next few weeks, Ms. Gass and her colleagues would find several more mutations in the same gene, called progranulin, that caused FTD. "We were finding about three mutations a day," she says. "It was the best feeling ever. It's why I chose a career in science."

As rare as the achievement was, she had someone who could relate to it: Matt Baker, a senior research technologist also in Dr. Hutton's lab. Mr. Baker experienced the same joy eight years earlier. In 1998, he found the first genetic cause for FTD, a mutation in a gene that produces a protein called tau.

"I was more excited this time around, perhaps even more so than Jennifer, who initially made the discovery, because of the effect the first discovery had on the group," Mr. Baker says. "It had an incredible impact on research in our field, and it generated grant funding for our lab. I know this latest discovery will have a similar effect."

The secret to success
Mr. Baker says Mayo's strong clinical practice is the key because it attracts large numbers of research participants, which is vital for any genetics research. But Dr. Hutton says the technologists are an important piece of the puzzle.

"It's a testament to their skill," says Dr. Hutton. "It's very easy to miss small changes when you're looking at gene sequences day after day. Even though they'd seen so many DNA sequences, they didn't miss the one that counted."

The lab environment is also an important factor, Mr. Baker says, because Dr. Hutton expects research technologists to contribute to each project. The importance of these contributions are evident in the publications that result from the research, which frequently include Mr. Baker, Ms. Gass and their colleagues as co-authors. Indeed, Mr. Baker has established an impressive curriculum vitae during his 10 years with Dr. Hutton.

"Quite a few senior scientists in the field have commented that Matt's CV is comparable to the average professor," Dr. Hutton says.

That's another interesting aspect to this story. In Mr. Baker's case, the discoveries over the years have never given him the urge to pursue a doctoral degree. If anything, he is more comfortable in his career choice. "I love my job," he says. "It doesn't make sense for me to pursue a Ph.D.; it would change things too much."

But Ms. Gass is already pursuing a master's degree and the progranulin discovery has her thinking seriously about pursuing a doctorate. "It's a huge decision, but this experience has truly opened my eyes," she says.