New genetic mutations in the coding sequence of the GLT8D1 enzyme have been identified and linked to inherited amyotrophic lateral sclerosis (ALS), a study reports.
Researchers at the University of Sheffield in the U.K. and their collaborators found that these GLT8D1 gene variants prevented the normal functioning of the enzyme, which was associated with increased cellular toxicity and ALS-like motor deficits in experimental fish models.
The study, “Mutations in the Glycosyltransferase Domain of GLT8D1 Are Associated with Familial Amyotrophic Lateral Sclerosis,” was published in the journal Cell Reports.
The researchers conducted a genetic screen on two related individuals who had been diagnosed with ALS, also known as motor neuron disease (MND). The analysis revealed five potential genetic variants affecting different genes that could be responsible for ALS.
A third family member started to experience unilateral weakness and upper motor nerve cell dysfunction that was suggestive of ALS, although a definitive diagnosis was not reached. A genetic analysis of this family member also showed the same mutations previously identified in the GLT8D1 and ARPP21 genes.
To further explore the potential of these newly identified mutations in causing ALS, the team repeated the screen in samples from 103 familial and young sporadic ALS cases from the north of England.
They found four additional cases that had the same mutation as the one identified in the GLT8D1 gene in the previous family, as well as a new deleterious mutation in the same gene in another patient.
The presence of the GLT8D1 mutation alone was found to be associated with a 20.3 times increased risk of having ALS. When combined with mutations in the ARPP21 gene, the ALS risk from GLT8D1 mutations increases to up to 54.1 times.
“Genetic screening of MND patients is becoming increasingly important as we subclassify the disease and look for new therapeutic strategies,” Pamela Shaw, MD, director of the University of Sheffield’s Institute for Translational Neuroscience (SITraN) and the NIHR Sheffield Biomedical Research Centre, said in a university press release.
“Fundamental science breakthroughs, such as the discovery of this new gene that causes MND, are vitally important in helping us to understand the mechanisms of disease; paving the way to find potential new therapies,” said Shaw, the senior author of the study.
Assessment of the clinical presentation of ALS in these patients carrying GLT8D1 mutations showed that, in general, their disease manifestations were within the expected spectrum of ALS. However, patients who had both GLT8D1 and ARPP21 mutations had more severe disease than those who had only one gene affected.
To better understand the impact of GLT8D1 mutations, the team conducted several experiments with cells and fish models of ALS.
Their experiments revealed that the presence of the newly identified GLT8D1 mutations had a significant negative impact on cell metabolism and survival. In addition, the presence of GLT8D1 mutations or genetic inhibition of GLT8D1 enzyme production severely affected the mobility of Zebrafish embryos compared with healthy fish.
Until now, the role the GLT8D1 enzyme had been unclear, although it is present in several tissues in the body. With additional analysis, the team found that the identified mutations on the GLT8D1 gene prevented the normal activity of GLT8D1 enzyme, which could be directly related to the detected ALS-linked toxicity and motor cell impairment.
“Our functional data confirm the molecular toxicity of the discovered mutations in GLT8D1 in vitro and in vivo,” the researchers wrote.
“Our discovery places GLT8D1 glycosyltransferase activity firmly upstream in the pathogenesis of ALS, making it an attractive therapeutic target,” they added.