{"id":47167,"date":"2025-08-06T06:22:07","date_gmt":"2025-08-06T06:22:07","guid":{"rendered":"https:\/\/www.newsbeep.com\/au\/47167\/"},"modified":"2025-08-06T06:22:07","modified_gmt":"2025-08-06T06:22:07","slug":"dna-repair-other-genes-shape-huntingtons-disease-trajectory","status":"publish","type":"post","link":"https:\/\/www.newsbeep.com\/au\/47167\/","title":{"rendered":"DNA repair, other genes shape Huntington\u2019s disease trajectory"},"content":{"rendered":"

Both DNA repair and non-repair genes influence how and when Huntington\u2019s disease<\/a> develops, according to a study based on genetic data from more than 16,000 people with the disorder that also provides new potential targets for treatment.<\/p>\n

In addition, these findings reveal complex mechanisms behind CAG repeat expansions, the mutation underlying the disease, and provide clues to other disease-causing mechanisms.<\/p>\n

The study, \u201cGenetic modifiers of somatic expansion and clinical phenotypes in Huntington\u2019s disease highlight shared and tissue-specific effects<\/a>,\u201d was published in Nature Genetics.<\/p>\n

Recommended Reading<\/p>\n

\"A<\/p>\n

Huntington\u2019s disease mainly caused by changes in mismatch DNA repair system<\/p>\n

Huntington\u2019s is caused<\/a> by excessive repeats of a trio of nucleotides \u2014 a cytosine (C), an adenine (A), and a guanine (G) \u2014 in the HTT gene. This leads to the production of a longer-than-normal huntingtin protein that forms toxic clumps, causing nerve cell damage and motor, cognitive, and behavioral symptoms<\/a>. Nucleotides are DNA\u2019s building blocks.<\/p>\n

CAG repeat expansions are unstable, and\u00a0they can progressively lengthen<\/a> over time in certain cells through a process called somatic expansion. These somatic expansions are believed to contribute to disease onset and progression, with longer CAG repeats being associated with earlier onset and more severe disease.<\/p>\n

To better understand how somatic expansion occurs, a team of international researchers compared data from large genetic studies that looked at somatic CAG expansion in blood cells with those that focused on CAG length-driven Huntington\u2019s symptoms.<\/p>\n

Data came from 16,640 people diagnosed with Huntington\u2019s<\/a>, 5,379 of whom were participating in Enroll-HD (NCT01574053)<\/a>, the world\u2019s largest observational study on Huntington\u2019s.<\/p>\n

The researchers found somatic expansion in Huntington\u2019s is mainly caused by changes in the body\u2019s mismatch DNA repair system, rather than a general DNA damage response.<\/p>\n

During duplication of the two-strand DNA molecule, the wrong nucleotides are sometimes added to the newly formed DNA strand, creating a DNA mismatch with the adjoining, original strand. DNA mismatch repair genes normally help to correct this type of DNA damage, but in Huntington\u2019s, they contribute<\/a> to an expansion of the CAG repeats.<\/p>\n

The effects of variants in these repair genes, including MSH3, PMS2, and FAN1, showed \u201cunexpected complexity, including cell-type specificity,\u201d the researchers wrote.<\/p>\n

Some variants in these genes showed concordant effects significantly associated with both increased somatic expansion in blood cells and earlier symptom onset, but others did not.<\/p>\n

Given that symptoms are the result of nerve cell death, the lack of concordant effects of some variants suggests \u201cdifferentially modifiable regulation of these genes in brain and [blood] cells,\u201d the team wrote.<\/p>\n

Recommended Reading<\/p>\n

\"An<\/p>\n

Variant associated with a 10-year-earlier motor symptom onset<\/p>\n

Still, \u201cthe candidacy of MSH3 as a top target for therapeutic downregulation to reduce or block somatic expansion is bolstered by the frequent MSH3 [variants] concordantly associated with clinical hastening and increased somatic expansion, suggesting that blood repeat expansion could provide a molecular biomarker for assessing potential therapeutics,\u201d the researchers wrote.<\/p>\n

In addition to DNA repair genes, genes not related to DNA repair \u2014 including MED15, RRM2B, CCDC82, and TCERG1 \u2014 appeared to affect Huntington\u2019s clinical trajectory independently of somatic expansion.<\/p>\n

Our findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD \u2026 mechanisms beyond somatic expansion.<\/p>\n

Furthermore, a variant near the CAG repeat sequence, called CAA\/CCA-loss, was associated with a 10-year-earlier motor symptom onset, but did not increase the number of repeats in patients\u2019 blood cells, lab-grown human cells, or brain samples from deceased patients. This further emphasized the existence of a yet-unclear mechanism influencing disease onset beyond somatic expansion.<\/p>\n

A change in a non-coding part of the HTT gene, called the 5\u2032 untranslated region, was linked to somatic expansion in blood cells, but did not modify Huntington\u2019s clinical trajectory, \u201cstrongly implying an influence on somatic expansion in [blood] cells, but not neurons vulnerable to HD [Huntington\u2019s disease],\u201d the team wrote.<\/p>\n

These findings support a model where Huntington\u2019s is caused by excessive CAG repeats that suffer somatic expansion which is accelerated after a certain number of repeats. And when surpassing an even higher threshold of repeats, cell toxicity occurs.<\/p>\n

Strategies targeting processes in each of these sequential phases of Huntington\u2019s development may potentially help slow or halt the disease, the team noted. One such strategy is to prevent or slow CAG expansion.<\/p>\n

\u201cOur findings are directly relevant to the therapeutic suppression of expansion in DNA repeat disorders and provide additional clues to HD \u2026 mechanisms beyond somatic expansion,\u201d the researchers wrote.<\/p>\n","protected":false},"excerpt":{"rendered":"Both DNA repair and non-repair genes influence how and when Huntington\u2019s disease develops, according to a study based…\n","protected":false},"author":2,"featured_media":47168,"comment_status":"","ping_status":"","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[25],"tags":[64,63,336,128],"class_list":["post-47167","post","type-post","status-publish","format-standard","has-post-thumbnail","category-genetics","tag-au","tag-australia","tag-genetics","tag-science"],"_links":{"self":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/47167","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/comments?post=47167"}],"version-history":[{"count":0,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/posts\/47167\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media\/47168"}],"wp:attachment":[{"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/media?parent=47167"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/categories?post=47167"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.newsbeep.com\/au\/wp-json\/wp\/v2\/tags?post=47167"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}