A second gene mutation that causes an inherited form of amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, has been identified by Teepu Siddique, M.D., the Northwestern University researcher who, with collaborators from Massachusetts General Hospital, discovered the first ALS gene (ALS1) in 1993.
ALS is a terminal, progressive neuromuscular disease that renders the muscles of the body useless while leaving the mind unaffected. There is currently no effective treatment or cure for ALS. The newly identified gene mutation is responsible for a rare, slowly progressive, early-onset form of the disease, called juvenile inherited ALS (ALS2), discovered in highly inbred populations in North Africa and the Middle East.
Siddique and colleagues discovered the gene, located on chromosome 2q33, in four Tunisian and Saudi Arabian families. They first identified the location of the gene in 1994. Siddique and an international consortium of researchers reported the discovery of the aberrant gene in the Oct. 3 issue of Nature Genetics.
Their findings also clarify why clinicians previously confused ALS2 for another neurodegenerative disease called juvenile primary lateral sclerosis -- different mutations in the same gene are found in both individuals with ALS2 and those with juvenile primary lateral sclerosis, indicating that these conditions have a common genetic origin.
The accompanying editorial in the journal stated that the finding by Siddique et al. represents an important advance in the field of ALS research and in studies of neurodegeneration.
The gene for ALS2 is transmitted in an autosomal recessive pattern, i.e., the individual inherits copies of the same recessive gene from both parents. Symptoms of ALS2 manifest in the first or second decade of life and progress slowly for 10 to 15 years, akin to those of Stephen Hawking, the physicist.
In patients with the better known form of inherited ALS (ALS1), symptoms generally occur age 40 to 50 and patients die within five years. This form is autosomal dominant, that is, only one copy of the gene is required to cause the disease.
In its normal form, the gene responsible for ALS2 codes for a substance named alsin, a protein that plays an integral role in signaling pathways, intracellular trafficking and the organization of the cytoskeleton. Siddique and colleagues believe that, unlike ALS1, which is caused by a novel new property in a mutated gene, called a toxic gain of function, ALS2 results from loss of a physiologic function.
This means that the protein's functions can be predicted based on its structure, thus providing an opportunity for direct examination of the molecular consequence of the loss in model systems, Siddique said.
"The predicted sequence of the alsin protein may indicate a mechanism for motor-neuron degeneration because the predicted protein motifs are exchanges of GTP [guanosine triphosphate, a compound necessary for several important metabolic reactions] for small GTPase proteins. These GTPases are involved in cell signaling, such as transport of molecular cargo in cellular vesicles," Siddique said.
"Elucidation of protein partners interacting with alsin may inform us of basic mechanisms underlying neuronal degeneration. Identification of crucial players in this pathway may serve as therapeutic targets," Siddique said.
Siddique is the Abbott Labs Duane and Susan Burnham Research Professor, professor of neurology and of cell and molecular biology, director of the Les Turner ALS Foundation research and clinical programs in the Herbert C. and Florence M. Wenske Neurological Research Laboratories at Northwestern University Medical School and a member of the Northwestern University Institute for Neuroscience.
Collaborating on this study were researchers from the Medical School, as well as King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Brown University, Providence, R.I.; King Fahad Military Hospital, Jeddah, Saudi Arabia; Institute of Neurology, Tunis, Tunisia; and Duke University Medical Center, Durham, N.C.
This study was funded by grants from the National Institutes of Health, the Les Turner ALS Foundation, Grant Healthcare Foundation, the Michael Jordan Foundation and the Ralph and Marian Falk Medical Research Trust. Co-author Karim Ouahchi is a Muscular Dystrophy Association-funded fellow, and co-author Wu-Yen Hung is a Muriel Heller Fellow.
KEYWORDS: Amyotrophic lateral sclerosis, ALS, Lou Gehrig's disease, neurodegeneration