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FD is characterized by progressive renal insufficiency and cardio- and cerebrovascular involvement. Restricted access on Gb3-independent tissue injury experimental models has limited the understanding of FD pathophysiology and delayed the development of new therapies. Accumulating glycosphingolipids, mainly Gb3 and lysoGb3, are Fabry specific markers used in clinical follow up. However, recent studies suggest there is a need for additional markers to monitor FD clinical course or response to treatment. We used a gla-knockout zebrafish (ZF) to investigate alternative biomarkers in Gb3-free-conditions. RNA sequencing was used to identify transcriptomic signatures in kidney tissues discriminating gla-mutant (M) from wild type (WT) ZF. Gene Ontology (GO) and KEGG pathways analysis showed upregulation of immune system activation and downregulation of oxidative phosphorylation pathways in kidneys from M ZF. In addition, upregulation of the Ca2+ signaling pathway was also detectable in M ZF kidneys. Importantly, disruption of mitochondrial and lysosome-related pathways observed in M ZF was validated by immunohistochemistry. Thus, this ZF model expands the pathophysiological understanding of FD, the Gb3-independent effects of gla mutations could be used to explore new therapeutic targets for FD.<\/jats:p>","DOI":"10.3390\/ijms24010358","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:42:47Z","timestamp":1672116167000},"page":"358","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Gene Expression Analysis in gla-Mutant Zebrafish Reveals Enhanced Ca2+ Signaling Similar to Fabry Disease"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4797-0245","authenticated-orcid":false,"given":"Hassan Osman Alhassan","family":"Elsaid","sequence":"first","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"},{"name":"Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kon","family":"Tjeldnes","sequence":"additional","affiliation":[{"name":"Computational Biology Unit, Department of Informatics, University of Bergen, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2657-3504","authenticated-orcid":false,"given":"Mariell","family":"Rivedal","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7467-3724","authenticated-orcid":false,"given":"Camille","family":"Serre","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1783-5552","authenticated-orcid":false,"given":"\u00d8ystein","family":"Eikrem","sequence":"additional","affiliation":[{"name":"Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9160-4293","authenticated-orcid":false,"given":"Einar","family":"Svarstad","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3389-3194","authenticated-orcid":false,"given":"Camilla","family":"T\u00f8ndel","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"},{"name":"Department of Pediatrics, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans-Peter","family":"Marti","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"},{"name":"Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8842-534X","authenticated-orcid":false,"given":"Jessica","family":"Furriol","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"},{"name":"Department of Medicine, Haukeland University Hospital, 5021 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7859-9242","authenticated-orcid":false,"given":"Janka","family":"Babickova","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway"},{"name":"Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1186\/1750-1172-5-30","article-title":"Fabry disease","volume":"5","author":"Germain","year":"2010","journal-title":"Orphanet. 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