Researcher Collaborates to Identify New Gene Associated with ALS

A collaborative research effort spanning nearly a decade between researchers at Massachusetts General Hospital (MGH), MIT, the Broad Institute, King's College London (KCL) and other institutions has identified a novel gene for inherited amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease). This is the fourth gene associated with familial forms of the devastating neurological disorder. Two papers, published in the February 27 edition of Science, report mutations in FUS/TLS, a gene known to play a role in DNA repair and the regulation of gene expression. The mutations affect the behavior of the FUS/TLS protein within cells and lead to deposits of abnormal protein within motor neurons.

Nobel laureate H. Robert Horvitz, an investigator in the McGovern Institute for Brain Research at MIT and the Howard Hughes Medical Institute, collaborated on one of the studies led by researchers at MGH. The second study was conducted at King’s College London.

The MGH-led team found a series of mutations in a gene that interacts with biological pathways already implicated in ALS and other neurological diseases, resulting in familial ALS of differing inheritance patterns and varying severity. “This puts us closer to identifying the link between inherited and sporadic ALS as well as to new targets for drug design,” said Thomas Kwiatkowski, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead author of the report. MGH neurologist Robert Brown, MD, PhD, a long-term collaborator with Horvitz on ALS, was senior author.

ALS is a progressive neurodegenerative disease affecting motor neurons in the brain and spinal cord. Death of these nerve cells stops the transmission of neural impulses to muscle fibers, leading to weakness, paralysis and usually death from respiratory failure. Most cases of ALS are sporadic, with no evidence of inheritance, but 10 percent of cases appear to be inherited.

The current findings began when the MGH-led team analyzed a family from the Cape Verde islands in which four individuals developed a form of ALS primarily affecting their arms and legs but not their respiratory system. The patients’ maternal grandparents were first cousins, and the fact that many Cape Verde residents in small communities are closely related to each other increased the possibility that the disorder was caused by a recessive mutation inherited from both parents. The researchers screened affected and unaffected members of the family for instances in which both copies of a chromosomal region were identical. Affected family members were found to have such an area in a segment of chromosome 16, which previous studies by both groups had suggested might harbor an ALS gene.

Detailed sequencing of several candidate genes in that region identified an ALS-associated mutation in FUS/TLS, two copies of which were present in all four affected family members. Some apparently unaffected family members who also had two mutated copies had not reached the age where ALS symptoms typically appear. Several unaffected family members had a single copy of the variant, which was also seen in one unrelated Cape Verdean but not in a control group of 1,446 North American individuals.