SIGMAR1 Gene Mutation

SIGMAR1 Gene Mutation Linked To Juvenile ALS Development, Researchers Identify

From the Kingdom of Saudi Arabia, investigators have identified a mutation on the SIGMAR1 gene linked with the development of juvenile amyotrophic lateral sclerosis (ALS). Sigma-1 receptors, which are involved in motor neuron function and disease development, are affected by the gene variant, according to a study published in the Annals of Neurology, a journal of the American Neurological Association and the Child Neurology Society.

ALS, (Lou Gehrig's disease), is a progressive neurodegenerative disorder attacking brain and spinal cord nerve cells (neurons) which are responsible for controlling voluntary muscle movement. The degeneration of upper and lower motor neurons slowly weakens the muscles they control, which will ultimately lead to paralysis and death from respiratory failure.

The study revealed that yearly 1 to 3 per 100,000 individuals are affected by ALS, of which 90% of cases have no family history of the disease (sporadic ALS) with the remaining 10% of cases showing more than one family member being affected by it (familial ALS). Characterized by age of onset below 25 years, juvenile ALS is a rare and sporadic disorder which makes it hard to establish incidence rates. Having being diagnosed at 21, physicist, Professor Stephen Hawking is one of the most well known juvenile ALS patients.

Earlier investigations discovered that mutation of the superoxide dismutase 1 (SOD1) gene accounts for 20% of familial and 5% of sporadic ALS cases, while ALS2 and SETX gene mutations have been reported in juvenile ALS cases.

Dr. Amr Al-Saif from the King Faisal Specialist Hospital and Research Center in Riyadh, KSA, who is leading the present investigation, performed genetic testing on four patients from an ALS family who were diagnosed with juvenile ALS to study mutations suspected in disease development.

Using direct sequencing to detect the genetic variants, together with gene mapping on the DNA of study participants, researchers identified a shared homozygosity region in the affected individuals, and gene sequencing of SIGMAR1 showed a mutation affecting the encoded protein, Sigma-1 receptor. Cells with the mutant protein were not as resistant to programmed cell death (apoptosis) induced by stress to the endoplasmic reticulum.

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."