Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease reveal shared and tissue-specific effects

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 18, 2024

ABSTRACT Huntington’s disease (HD), due to expansion of a CAG repeat in HTT , is representative growing number disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers clinical landmarks somatic blood DNA reveal an underlying complexity cell-type specificity the mismatch repair-related processes influence timing. Differential capture non-DNA-repair gene by multiple measures cognitive motor dysfunction argues additionally for pathogenic processes. Beyond trans modifiers, differential effects are also illustrated at 5’-UTR variant promotes without influencing HD, while, even after correcting uninterrupted length, synonymous sequence change end dramatically hastens onset signs increasing expansion. Our findings directly relevant therapeutic suppression HD related provide route define individual neuronal cell types contribute different phenotypes.

Язык: Английский

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Identification of genetic modifiers of Huntington’s disease somatic CAG repeat instability by in vivo CRISPR-Cas9 genome editing

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 9, 2024

Huntington's disease (HD), one of >50 inherited repeat expansion disorders (Depienne and Mandel, 2021), is a dominantly-inherited neurodegenerative caused by CAG in

Язык: Английский

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In vivo CRISPR–Cas9 genome editing in mice identifies genetic modifiers of somatic CAG repeat instability in Huntington’s disease

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Huntington's disease, one of more than 50 inherited repeat expansion disorders1, is a dominantly neurodegenerative disease caused by CAG in HTT2. Inherited length the primary determinant age onset, with human genetic studies underscoring that driven length-dependent propensity to further expand brain3–9. Routes slowing somatic expansion, therefore, hold promise for disease-modifying therapies. Several DNA repair genes, notably mismatch pathway, modify mouse models10. To identify novel modifiers we used CRISPR–Cas9 editing knock-in mice enable vivo screening expansion-modifier candidates at scale. This included testing onset modifier genes emerging from genome-wide association as well interactions between providing insight into pathways underlying and potential therapeutic targets. A strategy identifies new contribute disease.

Язык: Английский

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trace: Tandem Repeat Analysis by Capillary Electrophoresis

Опубликована: Янв. 16, 2025

Version 0.5.0Description A pipeline for short tandem repeat instability analysis from fragment data.Inputs of fsa files or peak tables, and a user supplied metadata data-frame.The package identifies ladders, calls peaks, the modal repeats, then calculates metrics (e.g.

Язык: Английский

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RNA and condensates: Disease implications and therapeutic opportunities

Cell chemical biology, Год журнала: 2024, Номер 31(9), С. 1593 - 1609

Опубликована: Сен. 1, 2024

Язык: Английский

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Defining genes and pathways that modify huntingtin CAG repeat somatic instability in vivo

Nature Genetics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 22, 2025

Язык: Английский

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Poison exons: tuning RNA splicing for targeted gene regulation

Trends in Pharmacological Sciences, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

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Therapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases

DNA repair, Год журнала: 2025, Номер 147, С. 103817 - 103817

Опубликована: Фев. 15, 2025

Язык: Английский

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Tissue-Specific Effects of the DNA Helicase FANCJ/BRIP1/BACH1 on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders

International Journal of Molecular Sciences, Год журнала: 2025, Номер 26(6), С. 2655 - 2655

Опубликована: Март 15, 2025

Fragile X-related disorders (FXDs) are caused by the expansion of a CGG repeat tract in 5’-UTR FMR1 gene. The mechanism is likely shared with 45+ other human diseases resulting from expansion, process that has been shown to require key mismatch repair (MMR) factors. FANCJ, DNA helicase involved unwinding unusual secondary structures, implicated number processes including MMR. To test role FANCJ we crossed FancJ-null mice an FXD mouse model. We found loss resulted trend towards more extensive was significant for small intestine and male germline. This finding interesting implications raises possibility helicases may be important modifiers risk certain cell types.

Язык: Английский

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New Insights on Somatic Expression in Huntington's Disease Could Open Potential Therapeutic Avenues

Neurology Today, Год журнала: 2025, Номер 25(6), С. 19 - 25

Опубликована: Март 20, 2025

Язык: Английский

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