MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism
Rattachement africain : us, ph. Niveau de preuve : code pays fourni par la source.
Le résumé fourni par la source
Abstract X-linked dystonia parkinsonism (XDP) is a progressive adult-onset neurogenerative disorder caused by the insertion of a SINE-VNTR-Alu (SVA) retrotransposon in TAF1 gene. One element of the SVA is a tandem polymorphic CCCTCT repeat tract whose length inversely correlates with the age of disease onset. Previous observations that the repeat exhibits length-dependent somatic expansion and that XDP onset is modified by variation in DNA repair gene MSH3 indicated that somatic repeat expansion is an important disease driver. Here, we sought to uncover genetic modifiers of CCCTCT instability in XDP patients and to provide a mechanistic link between somatic instability and disease. We determined quantitative metrics of both repeat expansion and repeat contraction in blood. Using genetic association analyses of exome sequencing data, as well as directed sequencing of a variant MSH3 repeat, we found that MSH3 modifies repeat expansion and contraction in blood as well as age at onset. MSH3 alleles associated with earlier disease onset were associated with more expansion and less contraction. Conversely, alleles associated with later disease onset were associated with less expansion and more contraction. Notably, MSH3 repeat alleles were also similarly associated with expansion and contraction in brain tissues. Our findings provide key evidence that MSH3’s role(s) in CCCTCT repeat dynamics underlies its impact on clinical disease and indicate that therapeutic strategies to lower or inhibit MSH3 are predicted to both slow CCCTCT expansion and promote CCCTCT contraction, impacting the disease course prior to clinical onset.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- <i>MSH3</i> is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism
- Date Crossref
- 16/05/2025
- Éditeur
- openRxiv
- Type
- posted-content
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Broad Institute pays non établi dans la noticeOrganisation à but non lucratif
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Harvard University pays non établi dans la noticeUniversité ou école supérieure
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Massachusetts General Hospital Center for Genomic Medicine pays non établi dans la noticeÉtablissement de santé
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University of the Philippines Manila pays non établi dans la noticeUniversité ou école supérieure
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Makati Medical Center pays non établi dans la noticeÉtablissement de santé
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José R. Reyes Memorial Medical Center Department of Neurology pays non établi dans la noticeÉtablissement de santé
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Sunshine Care Foundation pays non établi dans la noticeOrganisation à but non lucratif
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College of Medicine Department of Pathology pays non établi dans la noticeUniversité ou école supérieure
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Movement Center of Makati Institute of Neurological pays non établi dans la noticeStructure de recherche
Broad Institute, Harvard University et Center for Genomic Medicine — Massachusetts General Hospital, avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.