{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T10:08:00Z","timestamp":1785838080079,"version":"3.56.0"},"reference-count":37,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T00:00:00Z","timestamp":1670025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hermann and Lilly Schilling-Stiftung f\u00fcr Medizinische Forschung im Stifterverband"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Fabry disease (FD) is a rare X-linked disease due to a multiverse of disrupting mutations within the GLA gene encoding lysosomal \u03b1-galactosidase A (AGAL). Absent AGAL activity causes the accumulation of complex glycosphingolipids inside of lysosomes in a variety of cell types and results in a progressive multisystem disease. Known disease-associated point mutations in protein-coding gene regions usually cause translational perturbations and result in premature chain termination, punctual amino acid sequence alterations or overall altered sequence alterations downstream of the mutation site. However, nucleotide exchanges at the border between introns and exons can affect splicing behavior and lead to abnormal pre-mRNA processing. Prediction with the Human Splicing Finder (HSF) revealed an indication of a significant change in splicing-relevant information for some known FD-associated GLA mutations. To experimentally determine the extent of the change, we made use of a minigene reporter assay and verified alternative splicing events for the exonic mutations c.194G&gt;T and c.358C&gt;G, which led to the usage of alternative donor splice sites at exon 1 and exon 2, respectively. In addition, the mutations c.548G&gt;T and c.638A&gt;T led to significant exon 4 skipping. We conclude that splicing phenotype analysis should be employed in the in vitro analysis of exonic GLA gene mutations, since abnormal splicing may result in a reduction of enzyme activity and alter the amenability for treatment with pharmacological chaperone (PC).<\/jats:p>","DOI":"10.3390\/ijms232315261","type":"journal-article","created":{"date-parts":[[2022,12,5]],"date-time":"2022-12-05T02:13:12Z","timestamp":1670206392000},"page":"15261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Abnormal Pre-mRNA Splicing in Exonic Fabry Disease-Causing GLA Mutations"],"prefix":"10.3390","volume":"23","author":[{"given":"Franziska","family":"Alfen","sequence":"first","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Putscher","sequence":"additional","affiliation":[{"name":"Neuroimmunology Section, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7015-3094","authenticated-orcid":false,"given":"Michael","family":"Hecker","sequence":"additional","affiliation":[{"name":"Neuroimmunology Section, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Uwe Klaus","family":"Zettl","sequence":"additional","affiliation":[{"name":"Neuroimmunology Section, Department of Neurology, University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7364-7791","authenticated-orcid":false,"given":"Andreas","family":"Hermann","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"},{"name":"Deutsches Zentrum f\u00fcr Neurodegenerative (DZNE) Rostock\/Greifswald, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Lukas","sequence":"additional","affiliation":[{"name":"Translational Neurodegeneration Section \u201cAlbrecht-Kossel\u201d, Department of Neurology, University Medical Center Rostock, 18147 Rostock, Germany"},{"name":"Center for Transdisciplinary Neurosciences Rostock (CTNR), University Medical Center Rostock, University of Rostock, 18147 Rostock, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1093\/qjmed\/hcq117","article-title":"Fabry disease: A review of current management strategies","volume":"103","author":"Mehta","year":"2010","journal-title":"QJM"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Wendrich, K., Whybra, C., Ries, M., Gal, A., and Beck, M. 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