Evidence map›Paper›PMID 41443196›Full record

ArticleAmerican journal of human genetics2026

MSH3 is a genetic modifier of somatic repeat instability in X-linked dystonia parkinsonism.

Alan Mejia Maza, Madison Hincher, Kevin Correia, Tammy Gillis, Ayumi Nishiyama, Ellen B Penney, Aloysius Domingo, Rachita Yadav, Micaela G Murcar, Patrick D Villafria Mercado and 16 more

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Article in American journal of human genetics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
4 · The record

Corrections and comments

  • Update of
    2025
5 · Who and what money

Authors and funding

26 authors.

Alan Mejia MazaDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Madison HincherDepartment of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Kevin CorreiaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Tammy GillisCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Ayumi NishiyamaDepartment of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Ellen B PenneyDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Aloysius DomingoDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Rachita YadavDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Micaela G MurcarDepartment of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Patrick D Villafria MercadoDepartment of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Justin S HanDepartment of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Ean P NorenbergDepartment of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Cara Fernandez-CeradoSunshine Care Foundation, Roxas City, Capiz, Philippines.
G Paul LegardaSunshine Care Foundation, Roxas City, Capiz, Philippines.
Michelle SySunshine Care Foundation, Roxas City, Capiz, Philippines.
Edwin L MuñozDepartment of Pathology, College of Medicine, University of the Philippines, Manila, Philippines.
Mark C AngDepartment of Pathology, College of Medicine, University of the Philippines, Manila, Philippines.
Cid Czarina E DiestaMovement Center of Makati Institute of Neurological, Neurosurgical and Behavioral Sciences (MINDS), Makati, Philippines.
Criscely GoDepartment of Neurology, Jose R. Reyes Memorial Medical Center, Metro Manila, Philippines.
Nutan SharmaDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
D Cristopher BraggDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Michael E TalkowskiDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA.
Marcy E MacDonaldDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jong-Min LeeDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Laurie J OzeliusDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Department of Neurology, The Collaborative Center for X-linked Dystonia-Parkinsonism, Massachusetts General Hospital, Charlestown, MA, USA. Electronic address: laurie.ozelius@mgh.harvard.edu.
Vanessa Chantal WheelerDepartment of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: vwheeler@mgh.harvard.edu.

Funding

Huntington's Disease Repeat Instability and PathogenesisR01NS049206 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI VANESSA C WHEELER · 2005 to 2026
$10.0M
Disease-Modifying Genes in Huntington's DiseaseR01NS091161 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI JAMES F GUSELLA · 2015 to 2026
$7.2M
Assembling the Genetic Architecture of X-linked Dystonia ParkinsonismR01NS102423 · NINDS · MASSACHUSETTS GENERAL HOSPITAL · PI David Cristopher Bragg, Clotilde Lagier-Tourenne · 2017 to 2026
$5.4M
NINDS NIH HHS R01 NS049206NINDS NIH HHS R01 NS091161NINDS NIH HHS R01 NS102423
6 · The paper itself

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. 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 individuals 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 and 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 the role of MSH3 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.

Indexed as

Dystonic DisordersGenes, ModifierGenetic Diseases, X-LinkedMutS Homolog 3 ProteinAdultAge of OnsetAllelesDNA Repeat ExpansionFemaleHistone AcetyltransferasesHumansMaleMiddle AgedTATA-Binding Protein Associated FactorsTranscription Factor TFIIDHistone AcetyltransferasesMSH3 protein, humanMutS Homolog 3 ProteinTATA-binding protein associated factor 250 kDaTATA-Binding Protein Associated FactorsTranscription Factor TFIIDcontractionexpansiongenetic modifiersMSH3repeatretrotransposonsomatic instabilityTAF1XDP

Identifiers

PMID41443196
PMCPMC12824618

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.