ArticleHuman molecular genetics2017
A modifier of Huntington's disease onset at the MLH1 locus.
Article in Human molecular genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers.
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Who cites it
78 citing papers in PubMed, 114 citations in OpenAlex.
- Baseline Variables Associated with Functional Decline in 2CARE, A Randomized Clinical Trial in Huntington's Disease.Journal of Huntington's disease · 2020Trial
- The HTT1a protein initiates HTT aggregation in a knock-in mouse model of Huntington's disease.Brain : a journal of neurology · 2026Article
- Structural insights into the MLH1-FAN1 interaction reveal an uncharacterized binding interface on MLH1.Nature communications · 2026Article
- Double strand breaks drive toxicity in a Huntington's disease mouse model with or without somatic expansion.Nature communications · 2026Article
- Genetic or pharmacological disruption of the MSH3 Y245/K246 IDL binding pocket slows CAG repeat expansion.NAR molecular medicine · 2026Article
- Article
- Enhancing the detection of HTT1a with neoepitope antibodies in mouse models of Huntington's disease.Brain communications · 2026Article
- DNA extrusion size determines pathway choice during CAG repeat expansion.Nucleic acids research · 2025Article
- Review
- Mechanism of trinucleotide repeat expansion by MutSβ-MutLγ and contraction by FAN1.Nature communications · 2025Article
- Genetic modifiers of somatic expansion and clinical phenotypes in Huntington's disease highlight shared and tissue-specific effects.Nature genetics · 2025Article
- CellPHIE: Integrating Pathway Discovery With Pooled Profiling of Perturbations Uncovers Pathways of Huntington's Disease, Including Genetic Modifiers of Neuronal Development and Morphology.bioRxiv : the preprint server for biology · 2025Article
- Multi-epitope immunocapture of huntingtin reveals striatum-selective molecular signatures.Molecular systems biology · 2025Article
- 3A or not 3A: Cytidine deaminases in the etiology of the CAG-repeat expansion diseases.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Genomic and Transcriptomic Approaches Advance the Diagnosis and Prognosis of Neurodegenerative Diseases.Genes · 2025Review
- Sex contribution to average age at onset of Huntington's disease depends on the number of (CAG)Scientific reports · 2024Article
- Review
- Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease.eLife · 2024Article
- A CAG repeat threshold for therapeutics targeting somatic instability in Huntington's disease.Brain : a journal of neurology · 2024Article
- Posttranscriptional regulation ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
13 authors at 7 institutions in 3 countries.
Funding
Abstract
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in HTT. Many clinical characteristics of HD such as age at motor onset are determined largely by the size of HTT CAG repeat. However, emerging evidence strongly supports a role for other genetic factors in modifying the disease pathogenesis driven by mutant huntingtin. A recent genome-wide association analysis to discover genetic modifiers of HD onset age provided initial evidence for modifier loci on chromosomes 8 and 15 and suggestive evidence for a locus on chromosome 3. Here, genotyping of candidate single nucleotide polymorphisms in a cohort of 3,314 additional HD subjects yields independent confirmation of the former two loci and moves the third to genome-wide significance at MLH1, a locus whose mouse orthologue modifies CAG length-dependent phenotypes in a Htt-knock-in mouse model of HD. Both quantitative and dichotomous association analyses implicate a functional variant on ∼32% of chromosomes with the beneficial modifier effect that delays HD motor onset by 0.7 years/allele. Genomic DNA capture and sequencing of a modifier haplotype localize the functional variation to a 78 kb region spanning the 3'end of MLH1 and the 5'end of the neighboring LRRFIP2, and marked by an isoleucine-valine missense variant in MLH1. Analysis of expression Quantitative Trait Loci (eQTLs) provides modest support for altered regulation of MLH1 and LRRFIP2, raising the possibility that the modifier affects regulation of both genes. Finally, polygenic modification score and heritability analyses suggest the existence of additional genetic modifiers, supporting expanded, comprehensive genetic analysis of larger HD datasets.
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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.