Summary: <\/strong>A new genomic diagnostics study has introduced an innovative \u201cRNA origami\u201d technique to accurately identify and measure high-stakes genetic errors. The research addresses a critical diagnostic blind spot: repeat expansion disorders, such as forms of muscular dystrophy, Huntington\u2019s disease, and amyotrophic lateral sclerosis (ALS), which are driven by repetitive sequences that multiply far beyond their normal length.<\/p>\n By stretching fragile RNA samples into labeled, usable nanostructures and passing them through microscopic glass holes called nanopores, the team achieved an unprecedented resolution capable of instantly distinguishing healthy tissue from disease state thresholds using only minuscule clinical samples.<\/p>\n Key Facts<\/strong><\/p>\n Source: <\/strong>University of Cambridge<\/p>\n Researchers have developed a technique that can identify errors caused by mutations linked to a range of genetic disorders, including forms of muscular dystrophy, Huntington\u2019s disease and amyotrophic lateral sclerosis (ALS), which could accelerate accurate diagnosis of these conditions.<\/strong><\/p>\n The technique, developed by researchers led by the University of Cambridge, uses RNA samples stretched into usable shapes and tiny glass holes known as nanopores, to analyse sections of RNA that have multiplied far beyond their normal length.<\/p>\n These expanded stretches interrupt the cell\u2019s machinery and can trigger conditions known as repeat expansion disorders, which affect approximately one in every 280 people. Scientists say that as many of 90% of people with these disorders are undiagnosed, which poses the need for a fast and affordable test for sizing the repeats.<\/p>\n The genomic DNA in our cells contains many stretches of simple repetitive sequences, but in repeat expansion disorders, the size of the expansion will often affect the onset and severity of the disease. However, measuring these expansions is notoriously difficult.<\/p>\n \u201cRNA is incredibly informative in terms of what it can tell you about the disorders we want to study, but it\u2019s also incredibly fragile and often challenging to study,\u201d said lead author Gerardo Pati\u00f1o\u2011Guill\u00e9n, from Cambridge\u2019s Cavendish Laboratory.<\/p>\n \u201cCurrent techniques were designed for DNA, so they often lose the information in RNA that signals disease. We wanted to fix that.\u201d<\/p>\n Measuring tandem repeat expansions usually relies on polymerase chain reaction (PCR), which many people will recall from the Covid-19 pandemic. However, PCR can distort the true length of the repeated section, while newer sequencing methods frequently encounter errors in the repeated sections.<\/p>\n Accurately sizing repeat expansions is important for diagnosis, because symptoms often depend on how large the repeat region has become. For example, people with around 50 repeats in the DMPK gene \u2013 the threshold for myotonic dystrophy type 1, the most common muscular dystrophy in adults \u2013 may only have mild symptoms. But any further increase in repeated sections can significantly raise the risk of a more severe form of the disease, which could be passed down to children.<\/p>\n In congenital central hypoventilation syndrome, another repeat expansion disorder, a difference of only six repeats can determine whether a newborn baby has normal breathing control or experiences dangerous respiratory failure during sleep.<\/p>\n Working with colleagues from the University of Belgrade in Serbia, the Cambridge researchers stretched RNA molecules into labelled nanostructures using short pieces of DNA, then passed the structures through a nanopore.<\/p>\n As the molecules travelled through the pore, they produced an electrical signal whose pattern corresponded to the RNA\u2019s shape, including how many repeats it contained.<\/p>\n This RNA origami method achieved a resolution of just 18 nucleotides \u2014 the essential building blocks of RNA and DNA\u2014 enough to tell apart healthy and disease\u2011associated repeat section.<\/p>\n The\u00a0results\u00a0are reported in the journal\u00a0Nature Communications<\/em>.<\/p>\n Pati\u00f1o\u2011Guill\u00e9n says the ability to detect such subtle differences with minimal RNA is particularly important given the tiny amounts of patient material often available in clinical settings. \u201cOne of the reasons our collaborators in Serbia were interested is that we only need extremely small amounts of RNA to get a good result,\u201d he said.<\/p>\n While the team have achieved promising results, in the lab, they are hoping to improve their technology to the point where it can be scaled to a commercial platform. The team has not yet tested patient samples, and the platform must be scaled up so that many nanopores operate in parallel \u2014 a prerequisite for producing results fast enough for routine diagnostics.<\/p>\n The University spin\u2011out company Cambridge Nucleomics, co\u2011founded by senior author Professor Ulrich Keyser, also from the Cavendish Laboratory, is developing the method into a diagnostics platform.<\/p>\n While the technique is unlikely to immediately replace routine PCR-based diagnostic tests, it could complement sequencing technology by providing fast, targeted tests capable of sizing the expansion for families known to carry repeat\u2011expansion disorders, or for clinicians needing quick answers.<\/p>\n In the longer term, Pati\u00f1o\u2011Guill\u00e9n sees potential for monitoring the response on disease-modifying therapies that are expected to be approved for repeat expansion disorders in the coming years.<\/p>\n \u201cWe have a very strong molecular platform,\u201d he said. \u201cWe\u2019re confident about what it can do in controlled samples. The next challenge is proving it works just as well in clinical material.\u201d<\/p>\n Funding: <\/strong>The research was supported in part by the European Research Council, the European Union, and the Engineering and Physical Sciences Research Council (EPSRC), part of UK Research and Innovation (UKRI). Gerardo Pati\u00f1o-Guill\u00e9n is a Member of Churchill College, Cambridge.<\/p>\n A<\/strong>: Because repeating genetic sequences are the ultimate cloaking device for standard laboratory machines. Traditional DNA tests like PCR act like a photocopier; when they encounter a phrase that repeats hundreds of times, the machine slips, stutters, and distorts the true length of the section. Since the severity of diseases like muscular dystrophy or ALS depends entirely on exactly how long<\/em> that repetition has grown, these minor reading errors cause thousands of patients to completely slip through the diagnostic cracks.<\/p>\n<\/div>\n A<\/strong>: RNA is incredibly informative but notoriously fragile and hard to handle. The Cambridge team solved this by using short pieces of DNA like structural staples, stretching the fragile RNA into a stable, highly predictable geometric shape. They then pull this labeled nanostructure through a microscopic glass hole called a nanopore. As the shape squeezes through, it disrupts an active electrical current. The unique dipping pattern of that electricity functions like a structural barcode, telling scientists exactly how many repeats the molecule contains.<\/p>\n<\/div>\n A<\/strong>: Not immediately. In its current laboratory stage, the platform is a highly precise, targeted tool rather than a mass-production replacement for basic PCR. Its immediate superpower is acting as a fast, targeted check for clinicians who need rapid answers or for families who already know they carry a repeat expansion disorder. In the long term, as the university spin-out Cambridge Nucleomics scales the system to run thousands of nanopores at once, it will also be used to monitor how effectively brand-new, disease-modifying therapies are working inside a patient\u2019s cells.<\/p>\n<\/div>\n<\/div>\n Author:\u00a0<\/strong>Sarah Collins<\/a>\n
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<\/picture>Key Questions Answered:<\/h3>\n
Editorial Notes:<\/h3>\n
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About this genetics and neurology research news<\/h2>\n
Source:\u00a0<\/strong>University of Cambridge<\/a>
Contact:\u00a0<\/strong>Sarah Collins \u2013 University of Cambridge
Image:\u00a0<\/strong>The image is credited to Neuroscience News<\/p>\n