{"doi":"10.1101/2024.08.13.607839","title":"Reconciling the effects of PMS2 in different repeat expansion disease models supports a common expansion mechanism","abstract":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":485668,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9491,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":322313,"name":"Carson J. Miller","orcid":"0000-0001-5459-7015","position":1,"is_corresponding":false},{"id":1329180,"name":"Alexandra K. Walker","orcid":null,"position":2,"is_corresponding":false},{"id":1328690,"name":"Kusala Anupindi","orcid":"0009-0004-0474-5330","position":3,"is_corresponding":false},{"id":248585,"name":"Bruce E. Hayward","orcid":null,"position":4,"is_corresponding":false},{"id":287780,"name":"Hernán Lorenzi","orcid":"0000-0003-0910-7894","position":5,"is_corresponding":false},{"id":246635,"name":"Karen Usdin","orcid":"0000-0003-3295-0740","position":6,"is_corresponding":false},{"id":322314,"name":"Xiao-Nan Zhao","orcid":"0000-0001-7281-3914","position":7,"is_corresponding":false},{"id":959753,"name":"Diego Antonio Jimenez","orcid":"0000-0002-7072-8449","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:07:52.536246Z","pmid":"39185211","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}