{"id":349839,"date":"2025-08-16T19:01:37","date_gmt":"2025-08-16T19:01:37","guid":{"rendered":"https:\/\/www.europesays.com\/uk\/349839\/"},"modified":"2025-08-16T19:01:37","modified_gmt":"2025-08-16T19:01:37","slug":"research-sheds-new-light-on-als-gene-mutation","status":"publish","type":"post","link":"https:\/\/www.europesays.com\/uk\/349839\/","title":{"rendered":"Research sheds new light on ALS gene mutation"},"content":{"rendered":"

Researchers at Yale School of Medicine said they\u2019ve solved a longstanding mystery of how mutations\u00a0in the C9ORF72 gene, a common genetic cause of amyotrophic lateral sclerosis<\/a> (ALS), may lead to toxic proteins.<\/p>\n

The findings suggest a new approach that could lead to the development of targeted therapies, the researchers said.<\/p>\n

Their study, \u201cAberrant splicing exonizes C9orf72 repeat expansion in ALS\/FTD<\/a>,\u201d was published in Nature Neuroscience.<\/p>\n

The discovery centers on mutations in C9ORF72, which are the most common genetic cause of ALS in European and North American populations. Although the causes of ALS<\/a> aren\u2019t fully understood, genetic mutations are known to be behind at least some cases of the disease.<\/p>\n

Within the\u00a0C9ORF72 gene, there\u2019s a region where a specific genetic sequence is normally repeated about a dozen times, but in ALS-causing mutations, the sequence is repeated hundreds of times. Researchers have known that this expanded genetic repeat leads to the production of toxic proteins that are thought to drive nerve cell damage in ALS.<\/p>\n

Recommended Reading<\/p>\n

\"Main<\/p>\n

ALS gene mutation contains a splicing puzzle<\/p>\n

Genes are made of exons \u2014 the sections that provide instructions to make proteins \u2014 and introns, which are regions that don\u2019t code for proteins but help regulate gene activity. Within a cell\u2019s DNA, genes contain exons interspersed with introns.<\/p>\n

When the gene is read to make protein, the entire gene is copied over into a temporary molecule called messenger RNA (mRNA). The mRNA then undergoes a process called splicing, where the introns are removed and the exons are strung together to form a sequence that is ultimately used to make proteins.<\/p>\n

The ALS-causing expansion mutation in C9ORF72 is located in an intron, which should normally be removed by splicing before the gene\u2019s mRNA is used to make any protein. And yet, it\u2019s been established that the mutation does lead to the production of abnormal proteins.<\/p>\n

Although these mechanisms are well established, they\u2019ve led to a conundrum for researchers: How could a mutation in an intron, a part of the gene that should be discarded, lead to a toxic protein?<\/p>\n

\u201cThese repeat proteins can interfere with a wide range of cell functions,\u201d Suzhou Yang, a PhD student in Yale\u2019s interdepartmental neuroscience program and lead author of the study, said in a university news story<\/a>. \u201cBut it has been a mystery how an intronic sequence, which is usually cut out and degraded, can be translated into these toxic proteins.\u201d<\/p>\n

Recommended Reading<\/p>\n

\"An<\/p>\n

Mystery solved<\/p>\n

The scientists figured out an answer to this puzzle. They determined that ALS-causing mutations in the C9ORF72\u00a0gene cause problems with the molecular machinery that normally controls mRNA splicing. As a result, part of an intron \u2014 including the mutation \u2014 instead turns into an exon and is included in the mature mRNA used to make protein.<\/p>\n

Junjie Guo, PhD, associate professor of neuroscience at Yale and senior author of the study, said this shows that \u201cwe must be cautious about categorizing mutations simply according to existing gene models, because it turns out, an intron does not always stay an intron.\u201d<\/p>\n

\u201cPart of the reason why it took us so long to find this is perhaps our static way of thinking about the genome and gene expression,\u201d Guo said. \u201cBut once we saw the RNA sequence, this abnormal process immediately jumped out to us.\u201d<\/p>\n

The discovery opens potential avenues for therapy, the researchers said. For starters, they showed that they could reduce expression of the mutant mRNA by using a small piece of genetic material to target a sequence that\u2019s only present when the intron is included.<\/p>\n

This allowed the treatment to target only the faulty mRNA without affecting the normal one, enabling cells to keep producing the healthy version of the protein.<\/p>\n

\u201cFrom the therapeutic perspective, we believe that this is a broadly applicable strategy of identifying unique sequences that could allow us to design therapeutic candidates to selectively target the disease-causing RNA,\u201d Guo said.<\/p>\n

The scientists hope to learn more about how mutations disrupt splicing to change an intron into an exon. Once those mechanisms are more fully understood, it may be possible to target them therapeutically.<\/p>\n

\u201cIt is most likely that there are additional cell-type-specific splicing regulators that determine the incorrect splice sites,\u201d Guo said. \u201cIf we can identify these regulators, they could become potential targets for manipulating and reversing these abnormal events.\u201d<\/p>\n","protected":false},"excerpt":{"rendered":"Researchers at Yale School of Medicine said they\u2019ve solved a longstanding mystery of how mutations\u00a0in the C9ORF72 gene,…\n","protected":false},"author":2,"featured_media":349840,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[3846],"tags":[267,70,16,15],"class_list":{"0":"post-349839","1":"post","2":"type-post","3":"status-publish","4":"format-standard","5":"has-post-thumbnail","7":"category-genetics","8":"tag-genetics","9":"tag-science","10":"tag-uk","11":"tag-united-kingdom"},"share_on_mastodon":{"url":"https:\/\/pubeurope.com\/@uk\/115039993414349399","error":""},"_links":{"self":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/349839","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/comments?post=349839"}],"version-history":[{"count":0,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/posts\/349839\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media\/349840"}],"wp:attachment":[{"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/media?parent=349839"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/categories?post=349839"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.europesays.com\/uk\/wp-json\/wp\/v2\/tags?post=349839"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}