Research finds key mutation in recessive ataxia

The discovery of a mutation which causes neurodegenerative disorders in fruit flies and a set of conditions known as recessive ataxia in humans was recently published by researchers at the Montreal Neurological Institute, in collaboration with the Baylor College of Medicine. The normal form of the gene encodes a vital part of the cell mitochondrion.

Isabelle Thiffault, who currently works full time on a stem cell research project at the Montreal Neurological Hospital, sat down with the Tribune to discuss the work. 

Thiffault began work on the project back in 2004, in a small county between Trois-Rivères and Quebec City. It was known that there was a genetic defect in the human population of that region, and the defect was a common trend throughout Quebec.

Her team began several different types of analysis, with a sample of 17 families.

 “We traced one of the chromosomes that had over 200 genes and began to search for the gene that was most likely to be associated with neuronal disease,” Thiffault said. “We started sequencing those genes but we didn’t find anything [at first].” 

Upon further analysis in 2006, as Thiffault and her team discovered and sequenced the six genes that expressed the mutation, a big surprise came from researchers at the Baylor College of Medicine. 

“We received a phone call from [them] and they told us that they did the same kind of analysis that we did, but on the Drosophila,” Thiffault said. 

The mutations discovered in the fruit flies encoded for mitochondrial methionyl-tRNA synthaetase (Aats-met). This fruit fly mutation led to progressive degeneration of photoreceptors in the eye, shortened life span, and reduced cell proliferation. 

Baylor College of Medicine researchers consulted the literature and found that the phenotype associated with the neurodegenerative disorders in fruit flies was linked to that region of the human genome where the human version of the Aats-met gene, MARS2 was located. 

“It was really perfect timing, because we were sequencing the same gene at the same time,” Thiffault said. 

According to the published article, MARS2 is a homologous human gene responsible for a type of disease called ataxia, which causes the loss of full control of bodily movements. This gene can be found in some French Canadian families. 

Currently, Thiffault is working on producing neuronic cultures from the skin of patients to find an explanation for why these genes, which are typically expressed in tissues, have an impact on certain kinds of neurons.

“We don’t understand why that gene is so important in the mitochondria and only has an impact on the brain, especially when it requires a lot of energy,” Thiaffault said. “So in producing these cultures, we could directly test them to see which have a positive impact on the phenotype.”  

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