{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,26]],"date-time":"2026-01-26T05:14:31Z","timestamp":1769404471267,"version":"3.49.0"},"reference-count":97,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2024,5,26]],"date-time":"2024-05-26T00:00:00Z","timestamp":1716681600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior (CAPES)"},{"name":"Funda\u00e7\u00e3o Carlos Chagas Filho de Amparo \u00e0 Pesquisa do Estado do Rio de Janeiro (FAPERJ)"},{"name":"Financiadora de Estudos e Projetos (FINEP)"},{"name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico (CNPq)"},{"name":"Universidade Federal do Estado do Rio de Janeiro (UNIRIO)"},{"name":"Universidade Federal do Rio de Janeiro (UFRJ)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Friedreich\u2019s Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys\u00ae), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.<\/jats:p>","DOI":"10.3390\/ijms25115796","type":"journal-article","created":{"date-parts":[[2024,5,27]],"date-time":"2024-05-27T10:14:07Z","timestamp":1716804847000},"page":"5796","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich\u2019s Ataxia"],"prefix":"10.3390","volume":"25","author":[{"given":"Loiane Mendon\u00e7a Abrantes","family":"Da Concei\u00e7\u00e3o","sequence":"first","affiliation":[{"name":"Laboratory of Bioinformatics and Computational Biology, Federal University of the State of Rio de Janeiro (UNIRIO), Avenida Pasteur, 296, Urca, Rio de Janeiro 22290-250, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucio Mendes","family":"Cabral","sequence":"additional","affiliation":[{"name":"Pharmaceutical Industrial Technology Laboratory, Federal University of Rio de Janeiro (UFRJ), Avenida Carlos Chagas Filho, 373, Cidade Universit\u00e1ria, Rio de Janeiro 21941-590, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel Rodrigues Coutinho","family":"Pereira","sequence":"additional","affiliation":[{"name":"Pharmaceutical Industrial Technology Laboratory, Federal University of Rio de Janeiro (UFRJ), Avenida Carlos Chagas Filho, 373, Cidade Universit\u00e1ria, Rio de Janeiro 21941-590, Brazil"},{"name":"Laboratory of Molecular Modeling & QSAR, Federal University of Rio de Janeiro (UFRJ), Avenida Carlos Chagas Filho, 373, Cidade Universit\u00e1ria, Rio de Janeiro 21941-590, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joelma Freire","family":"De Mesquita","sequence":"additional","affiliation":[{"name":"Laboratory of Bioinformatics and Computational Biology, Federal University of the State of Rio de Janeiro (UNIRIO), Avenida Pasteur, 296, Urca, Rio de Janeiro 22290-250, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,5,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1002\/1531-8249(199902)45:2<200::AID-ANA10>3.0.CO;2-U","article-title":"Friedreich\u2019s Ataxia: Point Mutations and Clinical Presentation of Compound Heterozygotes","volume":"45","author":"Schmitt","year":"1999","journal-title":"Ann. 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