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Genetic dissection of Huntington's disease modification by variation at RRM2B
Kiuk Lee1,2, Baehyun Shin1,2, Mingyu Kim1,2
1Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, United States.
Human Molecular Genetics
|October 15, 2025
Summary
Genetic variants near RRM2B, specifically the 8AM1 haplotype, influence Huntington's disease (HD) onset by altering RRM2B gene expression. These genetic factors interact to modify disease progression in HD patients.
Area of Science:
- Genetics
- Neurodegenerative Diseases
- Molecular Biology
Background:
- Huntington's disease (HD) pathogenesis involves somatic expansion of the HTT CAG repeat.
- Genetic factors are known to modify the onset of HD.
- The 8AM1 locus, near the RRM2B gene, has been identified as a potential modifier.
Purpose of the Study:
- To investigate the role of the 8AM1 locus and RRM2B gene variants in modifying Huntington's disease onset.
- To identify specific genetic variants within RRM2B and their functional consequences.
- To elucidate the mechanism by which RRM2B variants influence HD pathogenesis.
Main Methods:
- Capture sequencing of the RRM2B locus to identify genetic variants.
- Functional analyses in RRM2B knock-out cells and patient-derived lymphoblastoid cell lines (LCLs).
- Analysis of a large dataset of Huntington's disease onset data (n=12,982) to correlate variants with disease progression.
Main Results:
- A frameshift variant (rs1037699) disrupts a novel RRM2B isoform 2, potentially affecting mitochondrial function.
- 3' variants in RRM2B act as cis expression quantitative trait loci, influencing gene expression.
- Both 5' and 3' RRM2B variants independently contribute to the 8AM1 modifier effect, accelerating HD onset, especially when the frameshift variant is absent.
Conclusions:
- The 8AM1 haplotype modifies RRM2B expression in a cell- and context-dependent manner.
- Altered RRM2B expression, influenced by specific genetic variants, intersects with Huntington's disease pathogenesis.
- These findings highlight RRM2B as a key genetic modifier influencing the clinical trajectory of Huntington's disease.
