{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,3]],"date-time":"2026-05-03T03:04:07Z","timestamp":1777777447659,"version":"3.51.4"},"reference-count":66,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T00:00:00Z","timestamp":1763769600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NextGenerationEU\u2014MUR, Fondo Promozione e Sviluppo","award":["DM 737\/2021"],"award-info":[{"award-number":["DM 737\/2021"]}]},{"name":"NextGenerationEU\u2014MUR, Fondo Promozione e Sviluppo","award":["D75F21003210001"],"award-info":[{"award-number":["D75F21003210001"]}]},{"DOI":"10.13039\/501100002426","name":"Italian Telethon ONLUS Foundation, Rome, Italy","doi-asserted-by":"publisher","award":["GGP20092"],"award-info":[{"award-number":["GGP20092"]}],"id":[{"id":"10.13039\/501100002426","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2014NextGenerationEU","award":["PNRR-MR1-2022-12375730-CUP: D53C22003790006"],"award-info":[{"award-number":["PNRR-MR1-2022-12375730-CUP: D53C22003790006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Marinesco\u2013Sj\u00f6gren syndrome (MSS) is a rare autosomal recessive neuromuscular disorder marked by ataxia, muscle weakness, cataracts, and often intellectual and skeletal abnormalities. It is commonly caused by loss-of-function variants in the SIL1 gene, which impair binding immunoglobulin protein (BiP) function, leading to protein misfolding and activation of the unfolded protein response. In a 2-year-old patient with typical MSS symptoms, we identified a previously unreported c.1024G&gt;A (p.E342K) variant in SIL1 via whole-exome sequencing. The pathogenicity of this Sil1 variant was supported by evidence of structural changes revealed through in silico predictions, circular dichroism, and native gel electrophoresis. Patient-derived fibroblasts exhibited reduced Sil1 protein levels, likely due to misfolding and degradation, which was partially rescued by proteasome inhibition. Proteomics revealed a profile similar to known MSS cases and a distinctive MSS transcriptional signature. Ultrastructural analysis confirmed typical MSS features, such as autophagic vacuoles and lipid droplets. Although the p.E342K phenotype appears milder than the reference pathogenic variant R111X, our findings support the reclassification of this novel variant as pathogenic, in accordance with the American College of Medical Genetics and Genomics\/Association for Molecular Pathology (ACMG\/AMP) 2015 guidelines and the refinements proposed by the Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) recommendations. Furthermore, the overall evidence also provides important insights into the genotype\u2013phenotype correlation and the underlying pathogenic mechanism of the p.E342K variant.<\/jats:p>","DOI":"10.3390\/ijms262311310","type":"journal-article","created":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T09:02:07Z","timestamp":1763974927000},"page":"11310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel SIL1 Variant (p.E342K) Associated with Marinesco\u2013Sj\u00f6gren Syndrome Impairs Protein Stability and Function"],"prefix":"10.3390","volume":"26","author":[{"given":"Anna Giulia","family":"Ruggieri","sequence":"first","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7078-3253","authenticated-orcid":false,"given":"Nikolaos M.","family":"Marinakis","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, St. Sophia\u2019s Children\u2019s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece"},{"name":"Laboratory of Genetics, Department of Medicine, Democritus University of Thrace, 681 00 Alexandroupolis, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8234-6230","authenticated-orcid":false,"given":"Laura","family":"Amodei","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Potenza","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Afrodite","family":"Kampouraki","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, St. Sophia\u2019s Children\u2019s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7600-214X","authenticated-orcid":false,"given":"Faidon-Nikolaos","family":"Tilemis","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, St. Sophia\u2019s Children\u2019s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1197-7813","authenticated-orcid":false,"given":"Laura","family":"Pietrangelo","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianna","family":"Viele","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1281-607X","authenticated-orcid":false,"given":"Federica","family":"Di Marco","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1653-2194","authenticated-orcid":false,"given":"Piero","family":"Del Boccio","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6011-6548","authenticated-orcid":false,"given":"Federica","family":"Di Cintio","sequence":"additional","affiliation":[{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Department of Medical, Oral and Biotechnological Sciences, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nikoletta","family":"Selenti","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Medical School, St. Sophia\u2019s Children\u2019s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manthoula","family":"Valari","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Medical School, St. Sophia\u2019s Children\u2019s Hospital, National and Kapodistrian University of Athens, 115 27 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Federici","sequence":"additional","affiliation":[{"name":"Department of Innovative Technologies in Medicine and Dentistry, \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"},{"name":"Center for Advanced Studies and Technology (CAST), \u201cG. d\u2019Annunzio\u201d University of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4637-2606","authenticated-orcid":false,"given":"Adriana Erica","family":"Miele","sequence":"additional","affiliation":[{"name":"Department of Biochemical Sciences, 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Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,22]]},"reference":[{"key":"ref_1","unstructured":"Pagon, R.A., Adam, M.P., Ardinger, H.H., Wallace, S.E., Amemiya, A., Bean, L.J.H., Bird, T.D., Fong, C.T., Mefford, H.C., and Smith, R.J.H. (2010). Marinesco-Sjogren Syndrome. GeneReviews(R), University of Washington."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1111\/nan.12588","article-title":"Review: Protein misfolding diseases\u2014The rare case of Marinesco-Sjogren syndrome","volume":"46","author":"Chiesa","year":"2020","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Ichhaporia, V.P., and Hendershot, L.M. (2021). Role of the HSP70 Co-Chaperone SIL1 in Health and Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041564"},{"key":"ref_4","first-page":"e590","article-title":"Potential approaches for the treatment of Marinesco\u2013Sj\u00f6gren syndrome","volume":"1","author":"Viele","year":"2024","journal-title":"J. Innate Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s10048-015-0455-z","article-title":"Novel SIL1 mutations cause cerebellar ataxia and atrophy in a French-Canadian family","volume":"16","author":"Noreau","year":"2015","journal-title":"Neurogenetics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/cge.12230","article-title":"Phenotype-genotype correlations in patients with Marinesco-Sjogren syndrome","volume":"86","author":"Ezgu","year":"2014","journal-title":"Clin. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3634","DOI":"10.1093\/brain\/awt283","article-title":"SIL1 mutations and clinical spectrum in patients with Marinesco-Sjogren syndrome","volume":"136","author":"Krieger","year":"2013","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1038\/ng1677","article-title":"The gene disrupted in Marinesco-Sjogren syndrome encodes SIL1, an HSPA5 cochaperone","volume":"37","author":"Anttonen","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1312","DOI":"10.1038\/ng1678","article-title":"Mutations in SIL1 cause Marinesco-Sjogren syndrome, a cerebellar ataxia with cataract and myopathy","volume":"37","author":"Senderek","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"47557","DOI":"10.1074\/jbc.M208377200","article-title":"BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP","volume":"277","author":"Chung","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eaat5314","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: From mechanism to disease","volume":"368","author":"Walter","year":"2020","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"148742","DOI":"10.1016\/j.brainres.2023.148742","article-title":"Endoplasmic reticulum stress and its role in various neurodegenerative diseases","volume":"1826","author":"Singh","year":"2023","journal-title":"Brain Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1126\/science.1209038","article-title":"The unfolded protein response: From stress pathway to homeostatic regulation","volume":"334","author":"Walter","year":"2011","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"dmm033043","DOI":"10.1242\/dmm.033043","article-title":"SIL1, the endoplasmic-reticulum-localized BiP co-chaperone, plays a crucial role in maintaining skeletal muscle proteostasis and physiology","volume":"11","author":"Ichhaporia","year":"2018","journal-title":"Dis. Model. Mech."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1007\/s00401-013-1224-4","article-title":"Myopathy in Marinesco-Sjogren syndrome links endoplasmic reticulum chaperone dysfunction to nuclear envelope pathology","volume":"127","author":"Roos","year":"2014","journal-title":"Acta Neuropathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/ng1620","article-title":"Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP","volume":"37","author":"Zhao","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_17","unstructured":"(2024, June 10). ClinVar_Miner. Available online: https:\/\/clinvarminer.genetics.utah.edu\/variants-by-gene\/SIL1."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1002\/humu.23555","article-title":"ClinVar Miner: Demonstrating utility of a Web-based tool for viewing and filtering ClinVar data","volume":"39","author":"Henrie","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bracher, A., and Verghese, J. (2015). The nucleotide exchange factors of Hsp70 molecular chaperones. Front. Mol. Biosci., 2.","DOI":"10.3389\/fmolb.2015.00010"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"71","DOI":"10.36253\/ijae-13802","article-title":"Genotype-phenotype correlation and adaptive proteome reorganization in Marinesco-Sj\u00f6gren syndrome","volume":"126","author":"Ruggieri","year":"2022","journal-title":"Ital. J. Anat. Embryol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-019-0690-2","article-title":"Recommendations for application of the functional evidence PS3\/BS3 criterion using the ACMG\/AMP sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2019","journal-title":"Genome Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1093\/brain\/awab133","article-title":"INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH","volume":"144","author":"Hathazi","year":"2021","journal-title":"Brain"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"961","DOI":"10.1038\/ejhg.2008.22","article-title":"Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjogren syndrome","volume":"16","author":"Anttonen","year":"2008","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Gatz, C., Hathazi, D., Munchberg, U., Buchkremer, S., Labisch, T., Munro, B., Horvath, R., Topf, A., Weis, J., and Roos, A. (2019). Identification of Cellular Pathogenicity Markers for SIL1 Mutations Linked to Marinesco-Sjogren Syndrome. Front. Neurol., 10.","DOI":"10.3389\/fneur.2019.00562"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1002\/emmm.201303069","article-title":"SIL1, a causative cochaperone gene of Marinesco-Sojgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex","volume":"6","author":"Inaguma","year":"2014","journal-title":"EMBO Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1186\/s12967-024-05582-0","article-title":"Sil1-deficient fibroblasts generate an aberrant extracellular matrix leading to tendon disorganisation in Marinesco-Sjogren syndrome","volume":"22","author":"Amodei","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Potenza, F., Cufaro, M.C., Di Biase, L., Panella, V., Di Campli, A., Ruggieri, A.G., Dufrusine, B., Restelli, E., Pietrangelo, L., and Protasi, F. (2021). Proteomic Analysis of Marinesco-Sjogren Syndrome Fibroblasts Indicates Pro-Survival Metabolic Adaptation to SIL1 Loss. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222212449"},{"key":"ref_28","unstructured":"(2024, May 13). ClinVar, Available online: https:\/\/www.ncbi.nlm.nih.gov\/clinvar\/."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"D980","DOI":"10.1093\/nar\/gkt1113","article-title":"ClinVar: Public archive of relationships among sequence variation and human phenotype","volume":"42","author":"Landrum","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_31","unstructured":"(2024, June 12). Polymorphism_Phenotyping_v2. Available online: http:\/\/genetics.bwh.harvard.edu\/pph2\/."},{"key":"ref_32","first-page":"7.20.1","article-title":"Predicting functional effect of human missense mutations using PolyPhen-2","volume":"76","author":"Adzhubei","year":"2013","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_33","unstructured":"(2024, June 12). Mutation_Taster. Available online: https:\/\/www.mutationtaster.org\/."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: Mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2542","DOI":"10.1093\/bioinformatics\/btw192","article-title":"INPS-MD: A web server to predict stability of protein variants from sequence and structure","volume":"32","author":"Savojardo","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_37","unstructured":"(2024, May 20). Protein_Stability-MultiDimension. Available online: http:\/\/inpsmd.biocomp.unibo.it."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1042\/BJ20110500","article-title":"Structural analysis of the Sil1-Bip complex reveals the mechanism for Sil1 to function as a nucleotide-exchange factor","volume":"438","author":"Yan","year":"2011","journal-title":"Biochem. J."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"120209","DOI":"10.1016\/j.molliq.2022.120209","article-title":"Trifluoroethanol direct interactions with protein backbones destabilize \u03b1-helices","volume":"365","author":"Ander","year":"2022","journal-title":"J. Mol. Liq."},{"key":"ref_40","unstructured":"(2024, October 07). STRING. Available online: https:\/\/string-db.org\/."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","article-title":"The STRING database in 2023: Protein-protein association networks and functional enrichment analyses for any sequenced genome of interest","volume":"51","author":"Szklarczyk","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1093\/hmg\/ddp464","article-title":"Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome","volume":"19","author":"Zhao","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1021\/pr8008012","article-title":"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry","volume":"8","author":"Chen","year":"2009","journal-title":"J. Proteome Res."},{"key":"ref_44","unstructured":"(2025, November 04). Uniprot. Available online: https:\/\/www.uniprot.org\/uniprotkb\/Q9H173\/entry."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"D609","DOI":"10.1093\/nar\/gkae1010","article-title":"UniProt: The Universal Protein Knowledgebase in 2025","volume":"53","author":"UniProt","year":"2025","journal-title":"Nucleic Acids Res"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13023-020-01669-1","article-title":"Protein signature of human skin fibroblasts allows the study of the molecular etiology of rare neurological diseases","volume":"16","author":"Hentschel","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Li, C., Wang, X., Li, X., Qiu, K., Jiao, F., Liu, Y., Kong, Q., Liu, Y., and Wu, Y. (2019). Proteasome Inhibition Activates Autophagy-Lysosome Pathway Associated With TFEB Dephosphorylation and Nuclear Translocation. Front. Cell Dev. Biol., 7.","DOI":"10.3389\/fcell.2019.00170"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Farmer, B.C., Walsh, A.E., Kluemper, J.C., and Johnson, L.A. (2020). Lipid Droplets in Neurodegenerative Disorders. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00742"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1007\/s00204-014-1262-2","article-title":"Intracellular fibril formation, calcification, and enrichment of chaperones, cytoskeletal, and intermediate filament proteins in the adult hippocampus CA1 following neonatal exposure to the nonprotein amino acid BMAA","volume":"89","author":"Karlsson","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_50","unstructured":"(2023, January 10). Varsome. Available online: https:\/\/varsome.com\/."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1093\/bioinformatics\/bty897","article-title":"VarSome: The human genomic variant search engine","volume":"35","author":"Kopanos","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.1002\/ajmg.a.62338","article-title":"Phenotype-driven variant filtration strategy in exome sequencing toward a high diagnostic yield and identification of 85 novel variants in 400 patients with rare Mendelian disorders","volume":"185","author":"Marinakis","year":"2021","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_54","unstructured":"(2023, January 13). Primer-BLAST, Available online: https:\/\/www.ncbi.nlm.nih.gov\/tools\/primer-blast\/."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., and Madden, T.L. (2012). Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinform., 13.","DOI":"10.1186\/1471-2105-13-134"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Gasteiger, E., Hoogland, C., Gattiker, A., Duvaud, S., Wilkins, M.R., Appel, R.D., and Bairoch, A. (2005). Protein Identification and Analysis Tools on the Expasy Server, Humana Press.","DOI":"10.1385\/1-59259-890-0:571"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Giannotta, M., Fragassi, G., Tamburro, A., Vanessa, C., Luini, A., and Sallese, M. (2015). Prohibitin: A Novel Molecular Player in KDEL Receptor Signalling. BioMed Res. Int., 2015.","DOI":"10.1155\/2015\/319454"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1038\/ncb1751","article-title":"A traffic-activated Golgi-based signalling circuit coordinates the secretory pathway","volume":"10","author":"Pulvirenti","year":"2008","journal-title":"Nat. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Filocamo, M., Mazzotti, R., Corsolini, F., Stroppiano, M., Stroppiana, G., Grossi, S., Lualdi, S., Tappino, B., Lanza, F., and Galotto, S. (2014). Cell Line and DNA Biobank From Patients Affected by Genetic Diseases. Open J. Bioresour., 1.","DOI":"10.5334\/ojb.ab"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3164","DOI":"10.1016\/j.bbadis.2018.07.003","article-title":"PERK inhibition attenuates the abnormalities of the secretory pathway and the increased apoptotic rate induced by knockdown in HeLa cells","volume":"1864","author":"Capone","year":"2018","journal-title":"Biochim. Biophys. Acta-Mol. Basis Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/978-1-0716-3342-7_14","article-title":"Use of Native-PAGE for the Identification of Epichaperomes in Cell Lines","volume":"2693","author":"Roychowdhury","year":"2023","journal-title":"Methods Mol. Biol."},{"key":"ref_62","unstructured":"(2024, June 26). Sino-Biological. Available online: http:\/\/www.assay-protocol.com\/molecular-biology\/electrophoresis\/native-page.html."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbi.2024.07.008","article-title":"Transcriptomic and proteomic profiling of bi-partite and tri-partite murine iPSC-derived neurospheroids under steady-state and inflammatory condition","volume":"121","author":"Motaln","year":"2024","journal-title":"Brain Behav. Immun."},{"key":"ref_65","unstructured":"(2024, October 22). BigOmics-Analytics Omics Playground. Available online: https:\/\/bigomics.ch\/."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"D543","DOI":"10.1093\/nar\/gkae1011","article-title":"The PRIDE database at 20 years: 2025 update","volume":"53","author":"Bandla","year":"2025","journal-title":"Nucleic Acids Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11310\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T11:48:51Z","timestamp":1763984931000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/23\/11310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,22]]},"references-count":66,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["ijms262311310"],"URL":"https:\/\/doi.org\/10.3390\/ijms262311310","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,22]]}}}