Even with the entire human genome in hand, scientists can still have trouble rooting out the genes behind a disease. Consider amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease. One ALS-related gene mutation was found in 1993, but it affects only 1% of all ALS patients. Now, after a long dry spell, researchers have finally hit on a second. It's just as rare as the first, but it seems to be more closely related to aspects of ALS pathology found in all patients.
ALS typically appears in middle age, slowly destroying the motor neurons used to control muscles and usually killing a patient within 5 years of diagnosis. Five percent of all adult-onset ALS cases are known to have a strong genetic component, affecting multiple family members. But the rest seem to appear spontaneously in people with no prior family history. Scientists know little about what causes these sporadic cases. And the one known ALS gene in inherited ALS, called SOD1, doesn't seem to lead to neuronal death--the primary characteristic of ALS--so the link between this gene and the disease is still unclear.
Christopher Shaw, a neurologist at King's College London, started hunting for other ALS genes by recruiting patients who have the inherited form of the disease but not the SOD1 mutation. While screening 154 people with familial ALS, Shaw and his colleagues found four individuals in one family who shared the same mutation: a single changed base on chromosome 1. The base was located in the TDPB gene, which encodes a protein called TDP-43 whose function isn't clear. In 2006, scientists reported that in both inherited and sporadic ALS, this protein disappears from the nucleus and clumps up in the cytoplasm of brain and motor neurons.
To see whether TDPB might have a role beyond inherited ALS, Shaw's team sequenced the TDPB gene in 200 people from the United Kingdom and 172 from Australia with the sporadic form of the disease. They found two more people with different mutations in the same gene and didn't see it in more than 1200 people without ALS. Finding multiple mutations in the same gene is "pretty rare," says Shaw. All the mutations seem to have the same effect; they alter the part of the TDP-43 protein that interacts with other proteins, the group reports online today in Science. And when they created chicken embryos with a mutated TDPB gene, they found that some neurons and other cells died.
Shaw's next step is to insert this faulty TDPB gene into mice and see if it kills neurons in mammals. Brian Dickie, director of research development at the Motor Neurone Disease Association in Northampton, U.K., believes that these mouse models may offer other insights into ALS, too. "TDP-43 is also deposited in the neurons of people who have dementia," he says, "and, in a small number of ALS cases, dementia precedes loss of motor function." He wonders if Shaw's work will provide a better understanding not only of ALS mechanisms but also of common pathways between ALS and other neurologic diseases.