Mitochondrial genome mutations linked to ALS in genetic study
Findings could inform disease diagnosis, treatment
Mutations in the mitochondrial genome — the set of DNA instructions found inside mitochondria, the powerhouses of cells — may be linked to amyotrophic lateral sclerosis (ALS), a study found.
The findings open the door for new ways of diagnosing and treating the disease, researchers said.
“We aren’t saying these mutations cause the disease, just that they’re associated and should be part of the diagnostic panel,” Marcelo Briones, PhD, the study’s first author, said in a news story from the São Paulo Research Foundation, which provided him with grant support. “In future, they could be useful for gene therapy studies.”
The study, “Mitochondrial genome variants associated with amyotrophic lateral sclerosis and their haplogroup distribution,” was published in Muscle & Nerve. According to Briones, a professor at the Federal University of São Paulo in Brazil, it is “the first to associate mitochondrial genome mutations with ALS.”
Scanning the genome
ALS can be familial, meaning it is passed down in a family, or sporadic, occurring in patients who have no known history of the disease in their families. While genetic mutations are mostly linked to familial ALS, they are also found in the sporadic form of the disease.
All of the genes so far linked to ALS reside in the nucleus, a membrane-enclosed structure that contains the chromosomes with most of a cell’s genetic material. While damage to the mitochondria have been shown to contribute to ALS, no studies have looked for disease-causing mutations in their genome.
The researchers in Brazil, with collaborators in the U.S., ran a genome-wide association study (GWAS) to identify mutations in mitochondrial DNA that may be linked to ALS. This was done by scanning the mitochondrial genome of 1,965 people with ALS and 2,547 individuals without ALS (controls) to look for mutations that occur more or less frequently in those with the disease.
“It’s hard to obtain a large sample for ALS,” Briones said. To compensate for this limitation, the researchers drew on genetic data from patients diagnosed at centers of the New York Genome Center ALS Consortium. The consortium is a global network of experts that uses genomic sequencing, a way to read the complete set of DNA instructions, to better understand ALS.
“Because we were looking for associations, we used GWAS to establish a panel of candidates as a starting point for anyone interested in identifying targets for therapy,” said Fernando Antoneli, PhD, one of the study’s authors and a professor at the Federal University of São Paulo. “A study of causal relations is then conducted.”
The study identified 51 mutations in the mitochondrial genome that were significantly associated with ALS. Thirteen mutations were linked to a higher risk of ALS. The 38 other mutations were linked to a lower risk of ALS.
“Our study … suggests that these [mutations] could be included in routine genetic testing for ALS and that mitochondrial replacement therapy has the potential to serve as a basis for ALS treatment,” the researchers wrote. In mitochondrial replacement therapy, faulty mitochondria are replaced with healthy ones.
Briones noted a limitation of the study. “Our data was from patients in the United States who mainly had white ancestors,” he said.
Still, “sufficient statistical data [have] been presented to suggest that these [mutations] could be included in panels for ALS testing along with nuclear genome [mutations],” the researchers wrote.
About the Author
