{"doi":"10.1093/brain/awad203","title":"Post-transcriptional microRNA repression of <i>PMP22</i> dose in severe Charcot-Marie-Tooth disease type 1","abstract":"Copy number variation (CNV) may lead to pathological traits, and Charcot-Marie-Tooth disease type 1A (CMT1A), the commonest inherited peripheral neuropathy, is due to a genomic duplication encompassing the dosage-sensitive PMP22 gene. MicroRNAs act as repressors on post-transcriptional regulation of gene expression and in rodent models of CMT1A, overexpression of one such microRNA (miR-29a) has been shown to reduce the PMP22 transcript and protein level. Here we present genomic and functional evidence, for the first time in a human CNV-associated phenotype, of the 3' untranslated region (3'-UTR)-mediated role of microRNA repression on gene expression. The proband of the family presented with an early-onset, severe sensorimotor demyelinating neuropathy and harboured a novel de novo deletion in the PMP22 3'-UTR. The deletion is predicted to include the miR-29a seed binding site and transcript analysis of dermal myelinated nerve fibres using a novel platform, revealed a marked increase in PMP22 transcript levels. Functional evidence from Schwann cell lines harbouring the wild-type and mutant 3'-UTR showed significantly increased reporter assay activity in the latter, which was not ameliorated by overexpression of a miR-29a mimic. This shows the importance of miR-29a in regulating PMP22 expression and opens an avenue for therapeutic drug development.","journal":"Brain","year":2023,"id":347963,"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":11,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9576,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":448288,"name":"Seongsik Won","orcid":null,"position":1,"is_corresponding":false},{"id":290204,"name":"Roy Poh","orcid":null,"position":2,"is_corresponding":false},{"id":242883,"name":"Stéphanie Efthymiou","orcid":"0000-0003-4900-9877","position":3,"is_corresponding":false},{"id":242888,"name":"James M. Polke","orcid":"0000-0002-9091-7132","position":4,"is_corresponding":false},{"id":290195,"name":"Mariola Skorupinska","orcid":null,"position":5,"is_corresponding":false},{"id":748973,"name":"Julian Blake","orcid":null,"position":6,"is_corresponding":false},{"id":242884,"name":"Alexander M. Rossor","orcid":"0000-0003-4648-2896","position":7,"is_corresponding":false},{"id":433399,"name":"John J. Moran","orcid":null,"position":8,"is_corresponding":false},{"id":816395,"name":"Pinki Munot","orcid":"0000-0001-9900-798X","position":9,"is_corresponding":false},{"id":118015,"name":"Francesco Muntoni","orcid":null,"position":10,"is_corresponding":false},{"id":242885,"name":"Matilde Laurá","orcid":"0000-0001-8264-8676","position":11,"is_corresponding":false},{"id":329208,"name":"John Svaren","orcid":"0000-0003-2963-7921","position":12,"is_corresponding":false},{"id":242899,"name":"Mary M. Reilly","orcid":"0000-0003-0686-905X","position":13,"is_corresponding":false},{"id":242886,"name":"Menelaos Pipis","orcid":"0000-0003-0511-6515","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T01:12:01.859977Z","pmid":"37337674","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":[]}