Cag article

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Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. • Article • • 29 April 2023 Structure-forming CAG/CTG repeats interfere with gap repair to cause repeat expansions and chromosome breaks • ORCID: orcid.org/0000-0001-6547-3624 • • ORCID: orcid.org/0000-0002-1878-0610 • … • ORCID: orcid.org/0000-0002-1652-2917 Show authors Nature Communications volume 14, Article number: 2469 ( 2023) Expanded CAG/CTG repeats are sites of DNA damage, leading to repeat length changes. Homologous recombination (HR) is one cause of repeat instability and we hypothesized that gap filling was a driver of repeat instability during HR. To test this, we developed an assay such that resection and ssDNA gap fill-in would occur across a (CAG) 70 or (CTG) 70 repeat tract. When the ssDNA template was a CTG sequence, there were increased repeat contractions and a fragile site was created leading to large-scale deletions. When the CTG sequence was on the resected strand, resection was inhibited, resulting in repeat expansions. Increased nucleolytic processing by deletion of Rad9, the ortholog of 53BP1, rescued repeat instability and chromosome breakage. Loss of Rad51 increased contractions implicating a protective role for Rad51...

• Article • • 16 December 2019 Assessing average somatic CAG repeat instability at the protein level • ORCID: orcid.org/0000-0001-6235-4996 • ORCID: orcid.org/0000-0001-6744-2805 • • • • • ORCID: orcid.org/0000-0002-6605-9158 • • • … • Show authors Scientific Reports volume 9, Article number: 19152 ( 2019) Sandwich ELISA-based methods use Abs that target the expanded polyglutamine (polyQ) tract to quantify mutant huntingtin (mHTT). Using Meso Scale Discovery (MSD) assay, the mHTT signal detected with MW1 Ab correlated with polyQ length and doubled with a difference of only 7 glutamine residues between equivalent amounts of purified mHTTexon1 proteins. Similar polyQ length-dependent effects on MSD signals were confirmed using endogenous full length mHTT from brains of Huntington’s disease (HD) knock-in (KI) mice. We used this avidity bias to devise a method to assess average CAG repeat instability at the protein level in a mixed population of HTT proteins present in tissues. Signal detected for average polyQ length quantification at the protein level by our method exhibited a strong correlation with average CAG repeat length at the genomic DNA level determined by PCR method in striatal tissue homogenates from Hdh Q140 KI mice and in human HD postmortem cortex. This work establishes that CAG repeat instability in mutant HTT is reflected at the protein level. Huntington’s disease (HD) is a neurodegenerative disease due to a CAG trinucleotide repeat expansion Technologies allo...

• Article • • 23 June 2021 Precise CAG repeat contraction in a Huntington’s Disease mouse model is enabled by gene editing with SpCas9-NG • ORCID: orcid.org/0000-0002-7606-732X • ORCID: orcid.org/0000-0003-0260-7861 • • • • • • … • ORCID: orcid.org/0000-0001-9859-6217 Show authors Communications Biology volume 4, Article number: 771 ( 2021) The clustered regularly interspaced palindromic repeats (CRISPR)/Cas9 system is a research hotspot in gene therapy. However, the widely used Streptococcus pyogenes Cas9 (WT-SpCas9) requires an NGG protospacer adjacent motif (PAM) for target recognition, thereby restricting targetable disease mutations. To address this issue, we recently reported an engineered SpCas9 nuclease variant (SpCas9-NG) recognizing NGN PAMs. Here, as a feasibility study, we report SpCas9-NG-mediated repair of the abnormally expanded CAG repeat tract in Huntington’s disease (HD). By targeting the boundary of CAG repeats with SpCas9-NG, we precisely contracted the repeat tracts in HD-mouse-derived embryonic stem (ES) cells. Further, we confirmed the recovery of phenotypic abnormalities in differentiated neurons and animals produced from repaired ES cells. Our study shows that SpCas9-NG can be a powerful tool for repairing abnormally expanded CAG repeats as well as other disease mutations that are difficult to access with WT-SpCas9. Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) is an RNA-guided genome editing tool tra...

Abstract Background: There is emerging evidence that clinical and neuro-pathological manifestations of Huntington’s disease (HD) may occur in individuals with intermediate length cytosine-adenine-guanine (CAG) repeats (27–35 CAG repeats) in the Huntingtin ( HTT) gene. We aim to further define the clinical characteristics of individuals who possess CAG repeat lengths in this range. Methods: Data from the Cooperative Huntington’s Observational Research Trial (COHORT) were analyzed. Participants were categorized according to the number of CAG repeats into normal (≤26), intermediate (27–35) and HD (≥36) groups. The motor, cognitive and behavioral scores on the Unified Huntington’s Disease Rating Scale (UHDRS) were compared between the intermediate and normal groups. Results: Of 1985 individuals affected by HD or with a family history of HD who were genotyped, 50 (2.5%) had their larger CAG repeat in the intermediate range. There were statistically significant differences in scores of some motor, cognitive, and behavioral domains of UHDRS at baseline between normal and intermediate length CAG repeats. Furthermore, a significantly greater number of subjects with CAG repeats in the intermediate range reported at least one suicide attempt compared to the normal group. Discussion: Our findings of motor, cognitive and behavioral abnormalities in individuals with intermediate CAG repeats suggest the presence of subtle, but relevant, disease manifestations in patients with intermediat...

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