Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism
- 1Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD 20892 ,
- 2The TriLab Bioinformatics Group, Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, MD 20892 ,
Abstract
Expansion of a disease-specific tandem repeat is responsible for >45 Repeat Expansion Diseases (REDs). The expansion mutation in each of these diseases has different pathological consequences and most are currently incurable. If the underlying mechanism of mutation is shared, a strategy that slows repeat expansion in one RED may be applicable to multiple REDs. However, the fact that PMS2, a component of the MutLα mismatch repair complex, promotes expansion in some models and protects against it in others suggests that the expansion mechanisms may differ. We show here using mouse models of two REDs caused by different repeats that PMS2 has similar effects in both models, with the loss of PMS2 resulting in an increase in expansions in some tissues and a loss of expansion in others. This is consistent with a protective effect of PMS2 in the first case and a role in promoting expansion in the second. Furthermore, we show in mouse embryonic stem cells that lower levels of PMS2 promote expansion while higher levels protect against it, with the ability to promote expansion depending on the PMS2 nuclease domain. Our findings lend support to the hypothesis that REDs share a common expansion mechanism and provide insights into the processes involved. Significance statement Collectively the Repeat Expansion Diseases (REDs) represent a significant health burden. Since the consequences of the expansion mutation differ across diseases, therapeutic approaches that block the underlying mutation are appealing, particularly if the mechanism is shared. However, the conflicting effects of PMS2 loss in different RED models challenges this idea. Here we show using two different RED models that these disparate effects can be reconciled into a single model of repeat expansion, thus increasing confidence that the REDs do all share a common mutational mechanism.
Related
- Suction or filter feeder? Morphology supports a combined feeding mechanism in the Little Auk (Alle alle)
- Cooperative care as a candidate mechanism linking prolonged childhood and brain expansion in human evolution
- Cross-Tissue Inflammatory Convergence Supports a Putative Muscle-Brain Axis in Alzheimer's Disease
- ERBB4 Perturbation Supports a Developmental Cytoskeletal Reactivation Hypothesis in Alzheimer’s Disease
- Reach plans for grasping vs. placing objects evoke different neural dynamics within a shared cortico-cerebellar mechanism.
BibTeX
@article{miller2026reconciling,
title = {{Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism}},
author = {Carson J. Miller and Diego Antonio Jimenez and Alexandra Walker and Kusala Anupindi and Bruce E. Hayward and Hernán Lorenzi and Karen Usdin and Xiao-Nan Zhao},
journal = {PNAS Nexus},
year = {2026},
month = jun,
doi = {10.1093/pnasnexus/pgag228},
url = {https://doi.org/10.1093/pnasnexus/pgag228},
note = {Public domain},
}
RIS
TY - JOUR
TI - Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism
AU - Carson J. Miller
AU - Diego Antonio Jimenez
AU - Alexandra Walker
AU - Kusala Anupindi
AU - Bruce E. Hayward
AU - Hernán Lorenzi
AU - Karen Usdin
AU - Xiao-Nan Zhao
PY - 2026
DA - 2026/06/25
JO - PNAS Nexus
DO - 10.1093/pnasnexus/pgag228
UR - https://doi.org/10.1093/pnasnexus/pgag228
AB - Expansion of a disease-specific tandem repeat is responsible for >45 Repeat Expansion Diseases (REDs). The expansion mutation in each of these diseases has different pathological consequences and most are currently incurable. If the underlying mechanism of mutation is shared, a strategy that slows repeat expansion in one RED may be applicable to multiple REDs. However, the fact that PMS2, a component of the MutLα mismatch repair complex, promotes expansion in some models and protects against it in others suggests that the expansion mechanisms may differ. We show here using mouse models of two REDs caused by different repeats that PMS2 has similar effects in both models, with the loss of PMS2 resulting in an increase in expansions in some tissues and a loss of expansion in others. This is consistent with a protective effect of PMS2 in the first case and a role in promoting expansion in the second. Furthermore, we show in mouse embryonic stem cells that lower levels of PMS2 promote expansion while higher levels protect against it, with the ability to promote expansion depending on the PMS2 nuclease domain. Our findings lend support to the hypothesis that REDs share a common expansion mechanism and provide insights into the processes involved. Significance statement Collectively the Repeat Expansion Diseases (REDs) represent a significant health burden. Since the consequences of the expansion mutation differ across diseases, therapeutic approaches that block the underlying mutation are appealing, particularly if the mechanism is shared. However, the conflicting effects of PMS2 loss in different RED models challenges this idea. Here we show using two different RED models that these disparate effects can be reconciled into a single model of repeat expansion, thus increasing confidence that the REDs do all share a common mutational mechanism.
SN - 2752-6542
ER -