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These deletions cause local chromatin changes and anomalous expression of nearby transcripts FRG2A, DBET, and D4Z4. We discovered that FRG2A is part of a family of long noncoding RNAs (lncRNAs) expressed in skeletal muscle cells, with levels varying among patients. FRG2A localizes in the nucleolus and associates with repetitive DNA at ribosomal DNA (rDNA) loci and centromeres. Elevated FRG2A expression in FSHD cells alters the three-dimensional architecture of heterochromatin at the nucleolar periphery and reduces rDNA transcription and translation rates, resulting in decreased synthesis of skeletal muscle proteins. We also show that myoblasts from FSHD patients display reduced synthesis of skeletal muscle proteins during differentiation. Our results support a disease model in which nucleolar accumulation of D4Z4-driven lncRNA impairs protein synthesis and contributes to muscle wasting.<\/jats:p>","DOI":"10.1093\/nar\/gkaf643","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T07:58:40Z","timestamp":1750406320000},"source":"Crossref","is-referenced-by-count":10,"title":["Nucleolar FRG2 lncRNAs inhibit rRNA transcription and cytoplasmic translation, linking FSHD to dysregulation of muscle-specific protein synthesis"],"prefix":"10.1093","volume":"53","author":[{"given":"Valentina","family":"Salsi","sequence":"first","affiliation":[{"name":"Metabolic and Neural Sciences University of Modena and Reggio Emilia Department of Biomedical, ,\u00a0 Modena\u00a041125 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Losi","sequence":"additional","affiliation":[{"name":"Metabolic and Neural Sciences University of Modena and Reggio Emilia Department of Biomedical, ,\u00a0 Modena\u00a041125 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2324-086X","authenticated-orcid":false,"given":"Bruno","family":"Fosso","sequence":"additional","affiliation":[{"name":"Biotechnology and Environment, University of Bari A. 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Moro Department of Biosciences, ,\u00a0 Bari\u00a070121 ,","place":["Italy"]},{"name":"Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies , Consiglio Nazionale delle Ricerche, Bari\u00a070126 ,","place":["Italy"]},{"name":"Consorzio Interuniversitario Biotecnologie , Trieste 34148,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony K","family":"Henras","sequence":"additional","affiliation":[{"name":"Centre for Integrative Biology (CBI), University of Toulouse Molecular, Cellular and Developmental Biology Unit (MCD), , CNRS, UPS, Toulouse\u00a031400 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D","family":"Kaufman","sequence":"additional","affiliation":[{"name":"Cell and Cancer Biology, University of Massachusetts Chan Medical School Department of Molecular, , Worcester , MA 01605 ,","place":["United 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