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.

The researchers then fully sequenced the protein-coding regions of FUS/TLS in two families that previous research had implicated as having an ALS-associated gene on chromosome 16 and found distinct FUS/TLS mutations in affected members of both families. Analysis of the gene in 81 unrelated familial ALS cases and almost 300 sporadic cases led to finding a total of 13 different FUS/TLS mutations in 17 familial ALS families, but no mutations were found in the sporadic cases or the control group.

The researchers sought to validate their early data implicating FUS/TLS mutations by asking researchers at King’s College London, led by Christopher Shaw, MBChB, MD, to screen the families they had been studying. As described in their Science paper, the KCL team reported three mutations in eight apparently unrelated families and went on to characterize the effect of the mutations in cultured cells. They also identified deposits of FUS/TLS protein in motor neurons of three patients with FUS/TLS mutations, deposits absent from patients with SOD1 mutations or sporadic ALS.

The MGH-led team then analyzed brain tissue from one of its patient and also found abnormal deposits of the FUS/TLS protein in the nucleus of both neuronal and non-neuronal cells, along with degenerative changes typical of ALS. “Finding genes for rare and rapidly fatal diseases is extremely challenging – I can’t stress enough how important it has been to have this international collaboration involving so many dedicated scientists and physicians on both sides of the Atlantic,” said Kwiatkowski, an instructor in Neurology at Harvard Medical School.

“We’ve just begun to look at how these apparent FUS/TLS aggregates relate to the disease process – whether they contribute to neuronal damage or protect against it,” he continued. “We’re also developing a genetic test for mutations in this gene, which could help screen at-risk individuals and aid clinicians in diagnosis. It’s been wonderful working together to try to solve ALS, and I hope our continued cooperation will make even greater strides.”

Brown added, “This discovery identifies new pathways implicated in ALS and will almost certainly lead to new animal- and cell-based models for this disease, which should accelerate efforts to find a therapy for ALS.”

The MGH-based study was supported by grants from the National Institutes of Health, the Angel Fund, the ALS Therapy Alliance, the ALS Association, Project ALS, the Al-Athel ALS Research Foundation, the Pierre de Bourgknecht ALS Research Foundation and other funders. Kwiatkowski and Brown have applied for a patent covering FUS/TLS mutations in ALS, and Brown is a co-founder of AviTx Inc., a company working to develop ALS therapies.

Additional co-authors of the MGH Science paper are E. Tamrazian, A. Davis, B. Hosler, Diane McKenna-Yasek, Peter Sapp, and Charles Venderburg, PhD, MGH-MIND; Daryl Bosco, PhD, A. LeClerc, and John Landers, PhD, UMass School of Medicine; Carsten Russ, PhD, Broad Institute; James Gilchrist, MD, Rhode Island Hospital; Edward J. Kasarskis, MD, PhD, University of Kentucky; Theodore Munsat, MD, Tufts Medical Center; Paul Vladmanis and Guy Rouleau, MD, PhD, University of Montreal; Pietro Cortelli, MD, PhD, University of Bologna; Pieter de Jong, PhD, and Y. Yoshinaga, Children’s Hospital Oakland Research Institute; Jonathan Haines, PhD, Vanderbilt University; Margaret Pericak-Vance, PhD, Miami Institute of Human Genetics; Jianhua Yan and Teepu Siddique, MD, Northwestern Feinberg School of Medicine; and N. Ticozza, University of Milan.

About Massachusetts General Hospital
Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

About the McGovern Institute
The McGovern Institute for Brain Research at MIT is led by a team of world-renowned neuroscientists committed to meeting two great challenges of modern science: understanding how the brain works and discovering new ways to prevent or treat brain disorders. The McGovern Institute was established in 2000 by Patrick J. McGovern and Lore Harp McGovern, who are committed to improving human welfare, communication and understanding through their support for neuroscience research. The director is Robert Desimone, formerly the head of intramural research at the National Institute of Mental Health

Source: McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT)