Development of Juvenile ALS associated with SIGMAR1 Gene Mutation

In a study published in the Annals of Neurology, investigators from the Kingdom of Saudi Arabia have identified that the development of juvenile amyotrophic lateral sclerosis (ALS) is associated with SIGMAR1 gene mutation. Variation in the SIGMAR1 gene affects the Sigma-1 receptors, which are a part of motor neuron function and disease development.
ALS (Lou Gehrig’s disease) being a progressive neurodegenerative disorder targets the brain and spinal cord nerve cells (neurons) responsible for voluntary muscle movement. Steady and progressive muscle weakening caused by the degeneration of upper and lower motor neurons eventually results in paralysis and fatality from respiratory failure.
According to the study, ALS affects 1 to 3 per 100,000 individuals annually. While 90% of cases have no family history of sporadic ALS, the rest 10% of cases have more than one family member with familial ALS.
Juvenile ALS is a rare and sporadic disorder with an onset of below 25 years, consequently increasing the difficulty of determining incidence rates. Renowned physicist Professor Stephen Hawking, who was diagnosed at the age of 21 years, is one of the most prominent juvenile ALS patients.
According to previous research, ALS2 and SETX gene mutations were seen in juvenile ALS cases, and superoxide dismutase 1 (SOD1) gene mutation made up for 5% sporadic and 20% familial ALS cases.
In order to study the mutations associated with ALS development, four juvenile ALS patients from an ALS family were genetically tested by study lead Dr. Amr Al-Saif from the King Faisal Specialist Hospital and Research Center in Riyadh, KSA.
Researchers used direct sequencing to identify genetic variants, and gene mapping of DNA to locate a shared homozygous region in the affected individuals. The encoded protein, Sigma-1 receptor was a product of mutation in the gene sequencing of SIGMAR1. Cells containing the mutant protein were not very resistant to endoplasmic reticulum stress-induced apoptosis (programmed cell death).
Dr. Al-Saif explains: “Prior evidence has established that Sigma-1 receptors have neuroprotective properties and animal models with this gene inactivated have displayed motor deficiency. Our findings emphasize the important role of Sigma-1 receptors in motor neuron function and disease. Further exploration is warranted to uncover potential therapeutic targets for ALS.”