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Differential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters

TitleDifferential Gene Expression in Late-Onset Friedreich Ataxia: A Comparative Transcriptomic Analysis Between Symptomatic and Asymptomatic Sisters
Publication TypeArticolo su Rivista peer-reviewed
Year of Publication2024
AuthorsPetrillo, S., Perna A., Quatrana A., Silvestri G., Bertini E., Piemonte F., and Santoro Massimo
JournalInternational Journal of Molecular Sciences
Volume25
Type of ArticleArticle
ISSN16616596
Abstract

Friedreich ataxia (FRDA) is the most common inherited ataxia, primarily impacting the nervous system and the heart. It is characterized by GAA repeat expansion in the FXN gene, leading to reduced mitochondrial frataxin levels. Previously, we described a family displaying two expanded GAA alleles, not only in the proband affected by late-onset FRDA but also in the younger asymptomatic sister. The molecular characterization of the expanded repeats showed that the affected sister carried two canonical uninterrupted GAA expended repeats, whereas the asymptomatic sister had a compound heterozygous for a canonical GAA repeat and an expanded GAAGGA motif. Therefore, we decided to perform RNA sequencing (RNA-seq) on fibroblasts from both sisters in order to understand whether some genes and/or pathways might be differently involved in the occurrence of FRDA clinical manifestation. The transcriptomic analysis revealed 398 differentially expressed genes. Notably, TLR4, IL20RB, and SLITRK5 were up-regulated, while TCF21 and GRIN2A were down-regulated, as validated by qRT-PCR. Gene ontology (GO) enrichment and network analysis highlighted significant involvement in immune response and neuronal functions. Our results, in particular, suggest that TLR4 may contribute to inflammation in FRDA, while IL20RB, SLITRK5, TCF21, and GRIN2A dysregulation may play roles in the disease pathogenesis. This study introduces new perspectives on the inflammatory and developmental aspects in FRDA, offering potential targets for therapeutic intervention. © 2024 by the authors.

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URLhttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85208561763&doi=10.3390%2fijms252111615&partnerID=40&md5=55951e3c81c1aeef4d3e8a303da5c532
DOI10.3390/ijms252111615
Citation KeyPetrillo2024