Cancer-linked Gene Plays Role in Neuron-wasting Disease

A gene with a penchant for breaking and reattaching in a cancer-causing way has another disease-promoting habit. Thomas Kwiatkowski, Robert Brown, and colleagues, working with researchers at King’s College London, have discovered that slight alterations in a cumbersomely named gene—fused in sarcoma/translocated in liposarcoma (FUS/TLS)—can cause heritable forms of the motor neuron–wasting disease amyotrophic lateral sclerosis (ALS). The findings appear in the Feb. 27 Science.

Researchers have known for decades that ALS, also known as Lou Gehrig’s disease, runs in families. Indeed, the intriguing case of a seaman, his sister and two maternal uncles who all exhibited the telltale pattern of disease—cramps in one set of limbs with subsequent wasting that spread to all limbs—was reported in 1850, almost two decades before the disease was officially described by the French neurologist Jean-Martin Charcot. Yet for nearly a century and a half, almost nothing was learned about how familial ALS, which accounts for 10 percent of all cases, arises. In 1993, Brown and colleagues discovered that approximately 20 percent of people with familial ALS carry a mutation in the superoxide dismutase 1 (SOD1) gene. Since then, only a smattering of additional genes has been captured, each accounting for a very small percentage of cases. Indeed, part of the problem is that the defining feature of ALS—motor neuron collapse—may be brought about by any number of mutations.

“It will probably turn out that there are many genes involved,” said Brown, who until recently was an HMS professor of neurology at Massachusetts General Hospital. Each is likely to be present in only a very small fraction of families, and finding those families with enough affected individuals to study has been a thorny challenge.

The FUS/TLS gene might have been buried for decades more had such a family not presented itself to Kwiatkowski, HMS instructor in neurology at the Mass General Institute for Neurodegenerative Disease (MIND). Using a combination of gene-scouring techniques, he and colleagues analyzed the family, which included three sisters with ALS and their nine siblings, and uncovered a region on chromosome 16 that was mutated in all the siblings. The unaffected sibs carried one copy and the sisters carried two copies of the mutant sequence, suggesting it was causing their disease in a recessive manner (though further studies showed that the mutation mostly causes disease in a dominant fashion).

Sequencing all the genes in the region, the researchers found that the mutation occurs in the FUS/TLS gene. Given its previous association with cancer, the discovery came as a surprise.

“One of the things this study illustrates is the power of unbiased gene searches,” said Rudolph Tanzi, the Joseph P. and Rose F. Kennedy professor of child neurology and mental retardation at MGH, who was not involved in the study. “For years we had to pick candidate genes based on our favorite hypothesis and just test those genes, and 99.9 percent of the time we were wrong. Who would have guessed that this gene would be an ALS gene?”

“That’s the power of genetics—it leads you to places where your own intuition is blind,” said Brown, who recently moved to head the neurology department at the University of Massachusetts, Worcester.

How exactly the sequence-altered mutant causes ALS is not clear, though there are intriguing clues. For example, the FUS/TLS protein tends to reside primarily in the nucleus, where it binds RNA. But King’s College researchers, led by Christopher Shaw, found it in the cytoplasm of cells carrying a dominant version of the mutant gene, a finding confirmed by the HMS group (see image at left). “So the disease might be a function of the aggregation of protein,” said Brown.

That the protein’s involvement came to light at all is the result of some hard-earned good fortune. For years, Kwiatkowski had been studying ALS-affected families in hopes of finding disease-causing genes, but had come up empty handed. In 2005, a pair of sisters from Rhode Island came to his clinic with early signs of ALS—and a fascinating story. Their mother also had the disease and had lived with it for 14 years before dying of a heart ailment.

Working with Diane McKenna-Yasek, a nurse in his clinic, Kwiatkowski visited the sisters and their 10 siblings, one of whom also showed signs of disease. They collected blood and more snippets of family history. It turned out, the mother’s parents, who did not have ALS, had been first cousins, which raised the possibility that they had each carried and passed on a copy of a mutant gene to their daughter. Kwiatkowski also learned that the mother and her unaffected husband came from a small island in Cape Verde, which meant the husband might be a relative and a carrier.

A hypothesis formed in Kwiatkowski’s mind: might the familial ALS gene be inherited in a recessive manner? If so, all 12 siblings would carry at least one copy of the mutation. Using high-throughput microarrays for detecting common genetic variants called single-nucleotide polymorphisms (SNPs), Kwiatkowski and colleagues homed in on a region of chromosome 16 that appeared to be carried singly by nine siblings and doubly by the three affected sisters.

The swathe of DNA encompassed 56 genes. Kwiatkowski and his colleagues ranked the genes, putting those with the most relevant biological function at the top, and began sequencing them to see which held the mutation. Those in the bottom tier were given to a summer intern, an undergraduate from Smith College named Alexandra Davis. “It just so happened to include the ALS gene,” said Kwiatkowski.

He and his colleagues went on to uncover a total of 13 mutant versions of FUS/TLS in a total of 17 families. Though Kwiatkowski estimates that the gene may be mutated in about five percent of familial ALS cases, a better understanding of how the alterations cause disease could open the door to a more general understanding of how ALS arises.

“In the end, motor neurons die—and via the same cell death pathway,” he said. “At some point, all of the different causes have to converge on a common final pathway. Each new gene discovery puts us a step closer to that final pathway.”

Students may contact Thomas Kwiatkowski at tkwiatkowski@partners.org for more information.

Conflict Disclosure: RB is a cofounder of AviTx, Inc., which is developing ALS therapies.

Funding Sources: The National Institutes of Health. RB also receives support from the Angel Fund, the ALS Therapy Alliance, Project ALS, the Al-Athel ALS Research Foundation, and the Pierre L. de Bourgknecht ALS Research Foundation.