Newly Identified GLT8D1 Genetic Variants Linked to Familial ALS, Study Reveals

Newly Identified GLT8D1 Genetic Variants Linked to Familial ALS, Study Reveals

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.


  1. Dave Reckonin says:

    Very interesting.
    It begs the question:
    “Now you’ve found it, what are you going to do with it?”

  2. Carol Mongiello says:

    So if a family member has one or both genes for als what purpose would that serve if the rest of the family had genetic testing done as there is no cure?

    • jeffrey woloshin says:

      reproductive issues life planning insurance policies if possible and career decisions as well as a need to know and personal empowerment jeff woloshin

  3. Nick says:

    Please translate some of this findings in actual new therapy to treat this death sentence of a disease.
    2 drugs on the market right now, both only prelong your life by months! Not years but a few months.
    Can we please do better? It’s 2019 and the progress made on ALS/MND is shameful.

  4. P says:

    I understand the frustration, but research takes time. Yes a new gene has been identified to be mutated in ALS patients. This is just the beginning, yet a step forward nonetheless.

    The gene encodes an enzyme, a protein required for modifying other proteins or chemicals, that when mutated loses its function. Reversing this loss of function is not a trivial matter.

    Pharmacologically, it would be difficult to reverse this loss of function. Normally drugs/medicine inhibit enzymes, rarely do they activate them. An alternative would be if another gene within the genome can perform a similar function as GLT8D1, then drugs that could induce the expression of this gene could be screened.

    Maybe we could look downstream of the mutated enzyme. What is it modifying in motor neurons? Is a certain target of GLT8D1 necessary and sufficient to protect motor neurons? If yes, can we artificially make the same change in that target of GLT8D1 with a drug?

    There’s also the possibility of gene therapy to either fix the mutated genome or reintroduce a working copy of GLT8D1. But what would be the target? Do we need to reintroduce/fix GLT8D1 in the brain, or are the peripheral motor neurons enough, what about the other cell types in the human body, do they all need a refurbished copy of the gene?

    This is not an exhaustive list of possibilities and I am not saying this to be pessimistic, or to say that science is a dead end. It just takes times to test all these approaches to come up with answers that may or may not be applicable to humans. It may seem discouraging, but science is moving forward every day. I agree that it’s not at the pace society can benefit from in the short term, but does that really make it shameful?

    Tens of thousands of graduate students tirelessly work long hours, through the night, weekends included, for less than minimum wage in sometimes abusive work environments to bring science just a bit further than it was. These same students will struggle to find jobs, and careers years after they graduate although they have dedicated a significant portion of their youth to improve society and the quality of life of patients. Some extremely bright and talented scientists will leave research because they can’t sustain a family. There is no job security and they are not valued for their capacity. All of this happens in the University setting. In addition, most big biopharmaceuticals won’t even waste capital on financing research on rare diseases, even less will perform research and development on rare neurological diseases. This is what I find to be shameful.

  5. Dave Reckonin says:

    Thanks P.
    We are all ecstatically excited to have a wider understanding of the huge volume of problems in medical research.

    I can understand your description of the frustrations of young under-paid researchers. However they have the opportunity of a likely long and healthy life.

    Most pALS would likely swap their current situation for decent health + minimum wage.

    There should be no ‘shame’ on either side of this debate.

    • P says:

      I’m glad I could provide some insight on the medical research field. There is an important disconnect between the public and the scientific community which is at the root of many frustrations.

      For example, many research publications cannot be accessed publicly despite relying entirely on public funds. There is a movement to change this. Scientific articles are not an easy read for the lay audience, but there should still be transparency.

      As for my point on undervalued researchers. It was to sensitize the public that talented scientists are moving away from research positions, which is slowing progress and innovation in medical research. I foresee University-driven research efforts to dwindle if resources are not allocated to accommodate new graduates into society.

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