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Morpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseases

2025-10-11Artigo científico Acesso restrito
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dc.contributor.authorLaranjeira, Mateus
dc.contributor.authorOliveira, Jorge Miguel
dc.contributor.authorSantorelli, Filippo Maria
dc.contributor.authorMarchese, Maria
dc.contributor.authorNogueira, Célia
dc.date.accessioned2026-01-26T11:24:03Z
dc.date.available2026-01-26T11:24:03Z
dc.date.issued2025-10-11
dc.description.abstractMitochondrial diseases (MDs) are heterogeneous multisystemic disorders often caused by genetic defects in either nuclear or mitochondrial DNA. Although next-generation sequencing technologies have dramatically expanded the number of variants associated with these diseases, many remain variants of unknown significance (VUS). This review explores the utility of zebrafish (Danio rerio) as a vertebrate model system for studying mitochondrial dysfunction, with a focused analysis on the application of morpholino oligonucleotides (MOs) to functionally characterize and interpret VUS. MO-induced knockdown produces a transient suppression of target genes during zebrafish early development, recapitulating key MD phenotypes. Furthermore, rescue experiments involving co-injection of MO and either wild-type or mutant mRNA have proven useful to functionally assess the pathogenicity of specific variants. Specifically, while wild-type mRNA rescues the morphant phenotype, failure of mutant mRNA to do so confirms the variant’s pathogenic effect. This approach has successfully linked previously uncharacterized genes to MD and helped reclassify ambiguous variants. The use of MO-based strategies in zebrafish remains a valuable tool for variant interpretation and functional validation, bridging the gap between genomic data and clinical action, and ultimately reducing the diagnostic odyssey. Overall, this review places MO knockdown and rescue assays in zebrafish as a robust and versatile platform to address functional genomics in MD research.eng
dc.description.sponsorshipThis work was supported by national funds from FCT – Fundação para a Ciência e Tecnologia I.P. (2023.00457.BDANA - https://doi.org/10.54499/2023.00457.BDANA and 2023.12019.PEX - https://doi.org/10.54499/2023.12019.PEX). JMAO acknowledges support by FCT (2024.16934.PEX) and the European Regional Development Fund (NORTE2030-FEDER-02707400). FMS and MM are supported by the Italian Ministry of Health (Ricerca Corrente 2024).
dc.identifier.citationNeuromolecular Med. 2025 Oct 11;27(1):69. doi: 10.1007/s12017-025-08890
dc.identifier.doi10.1007/s12017-025-08890-w
dc.identifier.eissn1559-1174
dc.identifier.issn1535-1084
dc.identifier.pmid41075035
dc.identifier.urihttp://hdl.handle.net/10400.18/10763
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSpringer
dc.relationModeling mitochondrial diseases in Zebrafish: Functional Validation of Genetic Variants of Unknown Significance VUS and strategies to a therapy
dc.relation2023.12019.PEX
dc.relation2024.16934.PEX
dc.relation.hasversionhttps://link.springer.com/article/10.1007/s12017-025-08890-w
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subjectMitochondrial Diseases
dc.subjectMorpholino Oligonucleotides
dc.subjectZebrafish
dc.subjectVariants of Unknown Significance
dc.subjectRescue Experiments
dc.subjectDoenças Genéticas
dc.titleMorpholino Knockdown in Zebrafish: A Tool to Investigate the Functional Impact of Variants of Unknown Significance in Mitochondrial Diseaseseng
dc.typejournal article
dcterms.referenceshttps://static-content.springer.com/esm/art%3A10.1007%2Fs12017-025-08890-w/MediaObjects/12017_2025_8890_MOESM1_ESM.docx
dspace.entity.typePublication
oaire.awardTitleModeling mitochondrial diseases in Zebrafish: Functional Validation of Genetic Variants of Unknown Significance VUS and strategies to a therapy
oaire.awardURIhttp://hdl.handle.net/10400.18/10760
oaire.citation.issue1
oaire.citation.startPage69
oaire.citation.titleNeuroMolecular Medicine
oaire.citation.volume27
oaire.versionhttp://purl.org/coar/version/c_970fb48d4fbd8a85
relation.isProjectOfPublication96d853b0-e9d0-4067-aaf1-a9a3b742863e
relation.isProjectOfPublication.latestForDiscovery96d853b0-e9d0-4067-aaf1-a9a3b742863e

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