Rare Mutations Can Interact With Related Proteins to Promote ALS Progression, Study Shows

Rare Mutations Can Interact With Related Proteins to Promote ALS Progression, Study Shows

Rare genetic mutations that affect functionally related proteins act in a synergistic manner to determine the course of ALS, a new genetic screening study shows. It also points to several new mutations that might lead to this disease.

“We provide evidence for a number of entirely novel genetic variants of ALS caused by mutations in RNA-binding proteins,” its researchers write. “Moreover we show that these mutations act synergistically with each other and with C9ORF72 expansions to modify the clinical phenotype [characteristics] of ALS. A key finding is that this synergy is present only between functionally interacting variants.”

The study, “Targeted Genetic Screen in Amyotrophic Lateral Sclerosis Reveals Novel Genetic Variants with Synergistic Effect on Clinical Phenotype,” was published in the journal Frontiers in Molecular Neuroscience.

It is not fully understood what causes ALS. The disease often appears to be caused by a combination of factors and is considered sporadic. However, in 5 to 10 percent of patients, a pattern of familial inheritance can be observed, suggesting a genetic origin of the disease.

Genetic alterations or mutations in the sequences of the C9orf72 and SOD1 genes have been pinpointed as the main causes of inherited ALS, but other mutations can also be disease-causing.

By looking carefully into ALS-related genes, researchers have found that the majority of them encode proteins that are involved in RNA metabolism, and have a RNA-recognition motif that allows them bind to RNA molecules. This suggests that ALS may be triggered by malfunctions in the RNA metabolism.

To test this hypothesis, researchers with the Project MinE ALS Sequencing Consortium studied if genetic mutations in RNA-binding proteins or C9orf72-binding partners could cause and affect ALS clinical features.

They analyzed the genetic sequence of 274 RNA-binding proteins and known ALS genes in DNA samples collected from 103 ALS patients. The group included 13 cases of familial ALS caused by C9orf72 mutations, and 29 cases with no genetic cause identified. The remaining cases were in younger patients (average age at disease onset: 41) diagnosed with sporadic ALS.

“Our filtering strategy aimed to identify rare deleterious variants rather than common low-risk variants. We also screened for variants in known ALS genes to augment the analysis and validate our strategy,” the researchers wrote.

The team identified 12 new mutations in several ALS genes — ALS2, DCTN1, ELP3, EWSR1, SETX, SOD1, UNC13A, C9orf72, and VCP — which supported the effectiveness of their approach in detecting ALS-associated genetic variants. In total, they identified 90 rare mutations in ALS genes and RNA/C9orf72-binding proteins in 42 patients, six of whom carried more than one variant.

They confirmed that the new genetic variants are significantly more frequent in ALS patients compared to controls.

The number of variants per patient not was associated with disease progression. However, if a patient carried more than one mutation in RNA-binding proteins, or had mutations affecting both C9orf72 and C9orf72-binding partners, that patient was likely to experience a significantly faster disease progression.

The researchers believe that these findings support the oligogenic model of ALS, which suggests that rare variants of functionally interacting genes can act synergistically to promote disease progression.

“Our findings have significant implications for the design of ALS disease models and therapeutics,” the researchers concluded. “Many of the variants identified potentially represent novel causative ALS genes.”

8 comments

    • Alice Melão says:

      Dear Richard, This study adds new information on how this disease develops, which may give scientist new clues on how to fight it. Although it does not brings to us a new cure may makes us closer to one.

      • Charlie says:

        ‘fraid not Alice. This study adds more information to the ‘symptom identification’ file.
        In fact it does the opposite of what you suggest. It adds vast numbers of additional genes that ALS affects without giving any clues as to how those genes might be rehabilitated.
        In short, it makes the puzzle much harder to solve and it is a cruel deception to say this takes us any further forward.
        A step backwards occurred today, alas, with this information.

        No-one from the researchers is claiming and showing how,with this new data, a way to cure ALS has been discovered or even simply pointed out.

  1. Charlie says:

    “It is not fully understood what causes ALS.”

    It would be fairer and more scientific to say that ‘it is not understood IN ANY WAY what causes ALS.’

    We should try to realistic, rather than insidiously engendering misplaced optimism. Science and Reality will eventually take us forward.

  2. Dave Shuey says:

    Sorry Charlie, couldn’t disagree with you more. While some advances are more significant than others, all contribute to a growing understanding of the etiology of this horrible disease. Let’s not forget that while a mechanistic-based cure is the ultimate goal, just understanding the neural pathology and managing it is an equally valuable approach. For example, experiments like those described above have provided evidence of protein aggregation in dying neurons. Treating the aggregation – without knowing the exact molecular cause – is a very valuable pursuit in itself. I personally am very excited about NAD+ based therapies. But to all – please don’t be discouraged by Charlie and keep fighting. A non-mechanism based neuroprotective therapy may prove to emerge as an effective management therapeutic sooner than we think.

  3. Charlie says:

    “A non-mechanism based neuroprotective therapy may prove to emerge as an effective management therapeutic sooner than we think.”

    Is there an English way of expressing this so folks might understand what it means?

  4. Charlie says:

    “But to all – please don’t be discouraged by Charlie and keep fighting.”

    You have completely misunderstood me, Mr.Shuey. I am not here to discourage anyone but rather to attempt analysis of information and sometimes the many glib, happy-clappy quotations, put forward and their value to us. Realism, rather than misplaced optimism and/or psychotic cheerfulness, will stand us all in better stead.
    I put forward my own opinions and it matters to me not at all if you might disagree. No one will insist you agree with me. If I get technically incorrect there would and no doubt will be a huge line forming instantly to correct me.

    Re: “Sorry Charlie, couldn’t disagree with you more.”
    Please don’t apologise for disagreeing with me. I disagree with you on this but it hardly merits an apology from me.

    If you think that the discovery of additional affected genes somehow points to greater understanding of this barbaric disorder then I feel you are very much mistaken. My opinion is that given the increasing number of genes found misbehaving in pALS, the answer will not lie in rehabilitating them one by one, but by the discovery of a single headline therapy that rehabilitates them all at pretty much the same time.

    The more that improved technology helps us discover more affected genes, the more we see, not a way towards treatment but a confirmation that the problem is far greater than anyone previously imagined.
    For example, one of the first gene problems concerned SOD1, yet very little research is being done to silence or modify that gene and I suspect that it is because researchers are not fully convinced that dealing with it alone will take us further forward. This is why,I think, we see research being carried out in so many diverse areas.

    If I might put to you a comment that may be clearer than your “..A non-mechanism based neuroprotective therapy may prove to emerge as an effective management therapeutic sooner..”….what is clearly happening in research is akin to this…’You are trying to complete a 3000 piece jigsaw puzzle but you know that some pieces are missing but you don’t know how many. You have barely joined together half a dozen pieces and then someone them comes along with a box of ‘around’ 3000 additional pieces and tells you a) it’s probably a 6000 piece jigsaw puzzle, and b) some of the pieces are missing from the new box load, but they don’t know how many.’ This adds to the ‘symptom identification’ for the huge jigsaw solving difficulty.

  5. Dave Shuey says:

    Sure. “You don’t have to know what caused the pothole to patch it up.”

    For example, NAD+ is known to rescue neurons dying from intracellular misfolded protein aggregates. You don’t have to know what caused these cytotoxic aggregates (i.e. the mechanism) in order to clear them.

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