A collaborative research effort spanning nearly a decade between researchers at Massachusetts General Hospital (MGH) and King's College London (KCL) 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.
"We 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," says Thomas Kwiatkowski, MD, PhD, of the MassGeneral Institute for Neurodegenerative Disease (MGH-MIND), lead author of the MGH report. "This puts us closer to identifying the link between inherited and sporadic ALS as well as to new targets for drug design."
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 first gene associated with familial ALS, SOD1, was discovered in 1993 by a multi-institutional team led by Robert Brown, MD, PhD, senior author of the MGH paper. Formerly director of the Day Neuromuscular Research Laboratory at MGH-MIND, Brown is now professor and chair of Neurology at the University of Massachusetts Medical School.
Mutations in SOD1 are believed to cause up to 25 percent of familial ALS, and finding additional genetic causes has been challenging. Several rare mutations that cause atypical forms of the disorder have been identified, and the second gene associated with the classic form, VAPB, has been observed in a few families in Brazil. In 2008, mutations in a gene called TARDBP, leading to abnormal neuronal deposits of the associated protein, were found by the KCL team in another group of familial ALS patients.
The current findings began with the MGH team's analysis of 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.