{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T11:43:05Z","timestamp":1788003785813,"version":"build-2784847793"},"reference-count":26,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T00:00:00Z","timestamp":1721347200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Anderson\u2013Fabry disease (AFD) is an X-linked multisystemic disorder with a heterogeneous phenotype, resulting from deficiency of the lysosomal enzyme \u03b1-galactosidase A (\u03b1-Gal A) and leading to globotriaosylceramide systemic accumulation. Lysosomal storage is not the unique player in organ failure and different mechanisms could drive tissue damage, including endoplasmic reticulum (ER) stress and its related signaling pathway\u2019s activation. We identified a new missense variant in the signal peptide of \u03b1-GLA gene, c.13 A\/G, in a 55-year-old woman affected by chronic kidney disease, acroparesthesia, hypohidrosis, and deafness and exhibiting normal values of lysoGb3 and \u03b1GLA activity. The functional study of the new variant performed by its overexpression in HEK293T cells showed an increased protein expression of a key ER stress marker, GRP78, the pro-apoptotic BAX, the negative regulator of cell cycle p21, the pro-inflammatory cytokine, IL1\u03b2, together with pNFkB, and the pro-fibrotic marker, N-cadherin. Transmission electron microscopy showed signs of ER injury and intra-lysosomal inclusions. The proband\u2019s PBMC exhibited higher expression of TGF\u03b2 1 and pNFkB compared to control. Our findings suggest that the new variant, although it did not affect enzymatic activity, could cause cellular damage by affecting ER homeostasis and promoting apoptosis, inflammation, and fibrosis. Further studies are needed to demonstrate the variant\u2019s contribution to cellular and tissue damage.<\/jats:p>","DOI":"10.3390\/genes15070947","type":"journal-article","created":{"date-parts":[[2024,7,19]],"date-time":"2024-07-19T14:16:38Z","timestamp":1721398598000},"page":"947","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Missense Variant in the Signal Peptide of \u03b1-GLA Gene, c.13 A\/G, Promotes Endoplasmic Reticular Stress and the Related Pathway\u2019s Activation"],"prefix":"10.3390","volume":"15","author":[{"given":"Sabrina","family":"Bossio","sequence":"first","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Graecia\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ida Daniela","family":"Perrotta","sequence":"additional","affiliation":[{"name":"Department of Biology, Ecology and Earth Sciences, Centre for Microscopy and Microanalysis (CM2), University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2081-463X","authenticated-orcid":false,"given":"Danilo","family":"Lofaro","sequence":"additional","affiliation":[{"name":"e-Health Lab, Department of Mechanical, Energy, Management Engineering, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1887-2854","authenticated-orcid":false,"given":"Daniele","family":"La Russa","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3971-7378","authenticated-orcid":false,"given":"Vittoria","family":"Rago","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renzo","family":"Bonofiglio","sequence":"additional","affiliation":[{"name":"Kidney and Transplantation Research Center, Annunziata Hospital, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosita","family":"Greco","sequence":"additional","affiliation":[{"name":"Nephrology, Dialysis, and Kidney Transplant Unit, Annunziata Hospital, 87100 Cosenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7974-3792","authenticated-orcid":false,"given":"Michele","family":"Andreucci","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2989-2618","authenticated-orcid":false,"given":"Antonio","family":"Aversa","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Graecia\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"La Russa","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, Magna Graecia University, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2852-0919","authenticated-orcid":false,"given":"Anna","family":"Perri","sequence":"additional","affiliation":[{"name":"Department of Experimental and Clinical Medicine, University \u201cMagna Graecia\u201d, 88100 Catanzaro, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,7,19]]},"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 J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Tuttolomondo, A., Simonetta, I., Riolo, R., Todaro, F., Di Chiara, T., Miceli, S., and Pinto, A. (2021). Pathogenesis and Molecular Mechanisms of Anderson-Fabry Disease and Possible New Molecular Addressed Therapeutic Strategies. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221810088"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.ymgme.2017.09.004","article-title":"Contribution of Inflammatory Pathways to Fabry Disease Pathogenesis","volume":"122","author":"Rozenfeld","year":"2017","journal-title":"Mol. Genet. Metab."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1002\/humu.10212","article-title":"Human Gene Mutation Database (HGMD): 2003 Update","volume":"21","author":"Stenson","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1136\/jmedgenet-2013-101857","article-title":"A Systematic Review on Screening for Fabry Disease: Prevalence of Individuals with Genetic Variants of Unknown Significance","volume":"51","author":"Smid","year":"2014","journal-title":"J. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4549","DOI":"10.1021\/cr010166y","article-title":"Signal Peptidases","volume":"102","author":"Paetzel","year":"2002","journal-title":"Chem. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1038\/s41586-022-05638-5","article-title":"Visualization of Translation and Protein Biogenesis at the ER Membrane","volume":"614","author":"Gemmer","year":"2023","journal-title":"Nature"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Sun, S., Li, X., and Mariappan, M. (2023). Signal Sequences Encode Information for Protein Folding in the Endoplasmic Reticulum. J. Cell Biol., 222.","DOI":"10.1083\/jcb.202203070"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3608","DOI":"10.1021\/bi0360509","article-title":"Effect of Signal Peptide on the Stability and Folding Kinetics of Maltose Binding Protein","volume":"43","author":"Beena","year":"2004","journal-title":"Biochemistry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e4485","DOI":"10.1002\/pro.4485","article-title":"Signal Peptide Stabilizes Folding and Inhibits Misfolding of Serum Amyloid A","volume":"31","author":"Wu","year":"2022","journal-title":"Protein Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Smets, D., Smit, J., Xu, Y., Karamanou, S., and Economou, A. (2022). Signal Peptide-Rheostat Dynamics Delay Secretory Preprotein Folding. J. Mol. Biol., 434.","DOI":"10.1016\/j.jmb.2022.167790"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1089\/ars.2009.2485","article-title":"Role of the Unfolded Protein Response Regulator GRP78\/BiP in Development, Cancer, and Neurological Disorders","volume":"11","author":"Wang","year":"2009","journal-title":"Antioxid. Redox Signal"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.lfs.2019.04.022","article-title":"GRP78: A Cell\u2019s Response to Stress","volume":"226","author":"Ibrahim","year":"2019","journal-title":"Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/sj.embor.7400779","article-title":"Mediators of Endoplasmic Reticulum Stress-Induced Apoptosis","volume":"7","author":"Szegezdi","year":"2006","journal-title":"EMBO Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1016\/j.molmed.2012.06.010","article-title":"ER Stress-Induced Inflammation: Does It Aid or Impede Disease Progression?","volume":"18","author":"Garg","year":"2012","journal-title":"Trends Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e103","DOI":"10.1136\/jmg.40.8.e103","article-title":"Fabry Disease: Molecular Studies in Italian Patients and X Inactivation Analysis in Manifesting Carriers","volume":"40","author":"Morrone","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1111\/tpj.12737","article-title":"Reactive Oxygen Species-Provoked Mitochondria-Dependent Cell Death during Ageing of Elm (Ulmus pumila L.) Seeds","volume":"81","author":"Wang","year":"2015","journal-title":"Plant J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9213","DOI":"10.1073\/pnas.86.23.9213","article-title":"Physiological Role during Export for the Retardation of Folding by the Leader Peptide of Maltose-Binding Protein","volume":"86","author":"Liu","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1146\/annurev.biochem.73.011303.074134","article-title":"The Mammalian Unfolded Protein Response","volume":"74","author":"Kaufman","year":"2005","journal-title":"Annu. Rev. Biochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/s41423-021-00670-3","article-title":"An Update on the Regulatory Mechanisms of NLRP3 Inflammasome Activation","volume":"18","author":"Paik","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Debnath, P., Huirem, R.S., Dutta, P., and Palchaudhuri, S. (2022). Epithelial-Mesenchymal Transition and Its Transcription Factors. Biosci. Rep., 42.","DOI":"10.1042\/BSR20211754"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.ymgme.2011.06.007","article-title":"Higher Apoptotic State in Fabry Disease Peripheral Blood Mononuclear Cells.: Effect of Globotriaosylceramide","volume":"104","author":"Mucci","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Braunstein, H., Papazian, M., Maor, G., Lukas, J., Rolfs, A., and Horowitz, M. (2020). Misfolding of Lysosomal \u03b1-Galactosidase a in a Fly Model and Its Alleviation by the Pharmacological Chaperone Migalastat. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21197397"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100926","DOI":"10.1016\/j.ymgmr.2022.100926","article-title":"\u03b1-Gal A Missense Variants Associated with Fabry Disease Can Lead to ER Stress and Induction of the Unfolded Protein Response","volume":"33","author":"Consolato","year":"2022","journal-title":"Mol. Genet. Metab. Rep."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Oder, D., Vergho, D., Ertl, G., Wanner, C., and Nordbeck, P. (2016). Case Report of a 45-Year Old Female Fabry Disease Patient Carrying Two Alpha-Galactosidase A Gene Mutation Alleles. BMC Med. Genet., 17.","DOI":"10.1186\/s12881-016-0309-z"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lavalle, L., Thomas, A.S., Beaton, B., Ebrahim, H., Reed, M., Ramaswami, U., Elliott, P., Mehta, A.B., and Hughes, D.A. (2018). Phenotype and Biochemical Heterogeneity in Late Onset Fabry Disease Defined by N215S Mutation. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193550"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/7\/947\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:19:48Z","timestamp":1760109588000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/15\/7\/947"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,19]]},"references-count":26,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2024,7]]}},"alternative-id":["genes15070947"],"URL":"https:\/\/doi.org\/10.3390\/genes15070947","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,19]]}}}