Juvenile ALS, Lou Gehrig’s Disease Gene Mutation Identified

A mutation in a gene called SIGMAR1 is associated with the development of juvenile amyotrophic lateral sclerosis (ALS),

also known as Lou Gehrig’s Disease. Scientists from the Kingdom of Saudi Arabia (KSA) write about how they found that the

gene variant affects receptors that influence motor neurons and disease development in a paper due to be published today, 12

August, in the Annals of Neurology. They suggest the receptor, known as Sigma-1, could be a potential target for

therapeutic drugs.

ALS is a progressive, neurodegenerative disease that attacks motor neurons, cells in the brain and spinal cord that control

voluntary movement. As the disease progresses, the muscles get weaker, leading to paralysis and eventually death, as a result of

respiratory failure.

ALS occurs in between 1 and 3 per 100,000 of the population. 9 out of 10 cases do not have a family history of the disease, this

is known as sporadic ALS. In the other remaining cases, there is a history of at least one other family member with the disease,

and this is known as familial ALS.

Juvenile ALS is rare and first appears below the age of 25. Professor Stephen Hawking, the well-known physicist, was diagnosed

with juveline ALS when he was 21 years old.

Previous studies have found genes linked to ALS: for instance a mutation of SOD1 accounts for 20% of familial and 5% of

sporadic ALS, and mutations in ALS2 and SETX have also been seen in juvenile ALS.

For this study, senior investigator Dr. Amr Al-Saif from the King Faisal Specialist Hospital and Research Center in Riyadh, KSA,

and colleagues, mapped the DNA and sequenced the genes of four people from a family with ALS, who had been diagnosed with

juvenile ALS.

They found affected individuals had two copies of a mutation of SIGMAR1 that affected the encoded protein, Sigma-1

receptor.

Further investigation revealed that cells with protein coded by the mutant gene were more likely to commit “suicide” (that is they

were less resistant to apoptosis, or programmed cell death), when that part of the cell in which the receptor resides (the

endoplasmic reticulum) came under stress.

Al-Saif said:

“Our findings emphasize the important role of Sigma-1 receptors in motor neuron function and disease.”

Previous studies have already shown Sigma-1 receptors have a role in protecting neurons, and animal studies have shown when

this gene is switched off, it weakens motor control.

“Further exploration is warranted to uncover potential therapeutic targets for ALS,” said Al-Saif.

Written by Catharine Paddock PhD

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