Amyotrophic lateral sclerosis, or ALS, is a horrible neurodegenerative disease that gradually robs patients of the ability to move and even breathe. Scientists have been trying for years to identify genetic causes of the condition, which is also known as Lou Gehrig's disease. Studies of families in which several members are affected - the traditional way to identify genes involved in disease processes - have pinpointed some suspicious mutations, but most cases of ALS occur sporadically in the population.
Now Stanford geneticist, Aaron Gitler, PhD, has hit upon a way to identify the de novo mutations (that is, mutations occurring in the egg or sperm of a patient's parents) that may contribute to the disease. To do so, he and postdoctoral scholar Alessandra Chesi, PhD, compared portions of the genome of ALS patients with those of his or her parents. The research (subscription required), which was conducted in collaboration with Stanford pathologist and developmental biologist Gerald Crabtree, MD, was published Sunday in Nature Neuroscience. From our release:
The researchers compared the sequences of a portion of the genome called the exome, which directly contributes to the amino acid sequences of all the proteins in a cell. (Many genes contain intervening, non-protein-coding regions of DNA called introns that are removed prior to protein production.) Mutations found only in the patient's exome, but not in that of his or her parents', were viewed as potential disease-associated candidates - particularly if they affected the composition or structure of the resulting protein made from that gene.
Using the exome sequencing technique, the researchers identified 25 de novo mutations in the ALS patients. Of these, five are known to be in genes involved in the regulation of the tightly packed form of DNA called chromatin - a proportion that is much higher than would have been expected by chance, according to Chesi.
Furthermore, one of the five chromatin regulatory proteins, SS18L1, is a member of a neuron-specific complex called nBAF, which has long been studied in Crabtree's laboratory. This complex is strongly expressed in the brain and spinal cord, and affects the ability of the neurons to form branching structures called dendrites that are essential to nerve signaling.
Neurons from mice with the mutant SS18L1 showed defects in their ability to extend and create new dendrites in response to stimuli, the researchers found. They now plan to sequence the SS18L1 gene in many other ALS patients. According to Chesi:
This is the first systematic analysis of ALS triads for the presence of de novo mutations. Now we have a list of candidate genes we can pursue. We haven't proven that these mutations cause ALS, but we've shown, at least in the context of SS18L1, that the mutation carried by some patients is damaging to the protein and affects the ability of mouse motor neurons to form dendrites.
Previously: In Stanford/Gladstone study, yeast genetics further ALS research and "Housekeeping" protein complex mutated in about 1/5 of all human cancers, say Stanford researchers