- A mutation in the sigma R1 gene has been identified as a cause of familial juvenile, or early-onset, ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease).
- The sigma R1 gene carries the genetic instructions for a protein that is known to have neuroprotective properties.
- The researchers suggest their data warrant further investigation of the sigma R1 gene in the study of ALS.
A mutation in the gene for a protein called sigma intracellular receptor 1 (sigma R1) has been identified as a cause of familial juvenile ALS (amyotrophic lateral sclerosis, or Lou Gehrig's disease), a team of researchers from Riyadh, Saudi Arabia, has reported.
Only about 5 percent of ALS cases are familial (inherited) with the other 95 percent occurring "sporadically," without a family history of the disease. The average age of onset of ALS in the United States and Europe is 56 to 63 years. Juvenile onset tends to manifest in the teens or early 20s, but symptoms can appear earlier. Such early onset is an extremely rare occurrence.
Previous studies have shown that sigma 1 receptors confer neuroprotective properties, and that research mice that lack the Sigma R1 gene exhibit symptoms of motor deficiency.
The researchers suggest that their data warrant further investigation of the sigma R1 gene and its associated protein as possible targets for ALS therapy development.
About the new findings
The research team performed genetic testing on four out of six people with juvenile-onset ALS who all are members of an extended family. They found all four shared a single mutation in the sigma R1 gene on chromosome 9; the mutation was not present in any of 271 individuals without ALS who comprised a control group.
Study of the newly identified mutation revealed that it affects the coding, or genetic instructions, carried by the gene for the sigma R1 protein.
Amr Al-Saif, Futwan Al-Mohanna and Saeed Bohlega, all at King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia, reported their findings online Aug. 12, 2011, in the Annals of Neurology. (See: A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis.)
The sigma R1 protein can be found throughout the body, including in the brainstem and spinal cord. It's known to perform a number of functions, one of which is to resist apoptosis. Apoptosis is programmed cell death that is triggered when cells are subjected to various forms of stress, and is thought to be one way that nerve cells die in ALS.
In a research model containing motor-neuron-like mouse cells, the investigators confirmed that cells with abnormal sigma R1 protein were less resistant to apoptosis than those cells with normal sigma R1 protein.
In the ALS online Genetics Database it's noted that mutations in the sigma R1 gene affect localization of the TDP43 and FUS proteins, abnormalities of which have been associated with ALS. (See FUS and ALS: What's the Connection?)
In addition, prior evidence has established that sigma 1 receptors have neuroprotective properties, Al-Saif said in a press release.
About sigma R1-associated ALS
In all six ALS-affected members belonging to the family with the sigma R1 mutation, spasms and weakness in the legs began at the age of 1 to 2 years. Onset of hand and forearm muscle weakness occurred at the age of 9 to 10 years. Respiratory function was unaffected, as were the muscles associated with talking and swallowing. Cognitive function was not impaired.
The researchers determined that inheritance of sigma R1-related ALS in the family is autosomal recessive, meaning a faulty gene must be inherited from each parent for a person to develop the disease.
The only other gene so far identified with juvenile ALS is senataxin (SETX), which also is located on chromosome 9.
MDA grantee Phillip Chance, then professor of neurology and pediatrics at the University of Washington, Seattle, led the international team that linked SETX with early-onset ALS. (Chance currently directs the Seattle Children's Research Institute's Center for Genetics and Development.) The team published its findings, DNA/RNA Helicase Gene Mutations in a Form of Juvenile Amyotrophic Lateral Sclerosis (ALS4), in the May 2004 issue of the American Journal of Human Genetics.
SETX-related ALS also is familial, but in contrast to sigma R1-associated ALS, it only requires a flawed gene from one parent for a person to inherit the disease. (This type of inheritance is called autosomal dominant).
Meaning for people with ALS
Researchers have become increasingly aware that ALS involves abnormal activity in any of a number of biological pathways in the body. Although a number of genes have been associated with the disease, the addition of sigma R1 to the list is likely to help shed additional light on the complex ALS disease process.
Because previous studies have shown that mutations in the sigma R1 gene affect localization of the ALS-associated TDP43 and FUS proteins and, in addition, possess neuroprotective properties, mutations in the gene could potentially play a role not only in juvenile ALS but in other forms of the disease as well.
The investigators noted that the study data support further exploration of sigma 1 receptors as potential therapeutic targets in ALS.