{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:27:43Z","timestamp":1783517263795,"version":"3.55.0"},"reference-count":32,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T00:00:00Z","timestamp":1782172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yuli Branch, Taipei Veterans General Hospital, Taiwan","award":["VHYL-110-09"],"award-info":[{"award-number":["VHYL-110-09"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: The genes encoding HSPA1A, HSPA1B, and HSPA1L, located in the MHC class III region at 6p21.3\u201322.1, a region implicated in susceptibility to schizophrenia, are critical regulators of neurodevelopmental processes and contribute to synaptic neuroprotection. This study investigated whether the HSPA1A, HSPA1B, and HSPA1L genes are associated with schizophrenia. Methods: We sequenced the coding regions of HSPA1A, HSPA1B, and HSPA1L from 100 patients with schizophrenia to identify genetic variants. Further, we conducted a genetic association analysis of three SNPs (rs9469057, rs142416335, and rs2075800) in the HSPA1L gene in 519 patients with schizophrenia and 1492 healthy controls from the Taiwan Biobank. We analyzed the function of the HSPA1L protein via immunoblotting. Results: We identified 17 coding variants, including 8 missense and 9 synonymous mutations, in 100 patients with schizophrenia. Three variants (HSPA1Lp.Ala8Pro, HSPA1Lp.Ala8Thr, and HSPA1Lp.Glu602Lys) in the HSPA1L gene did not exhibit any significant differences in allele or genotype frequencies between patients and control subjects. Notably, one ultra-rare missense mutation, HSPA1Lp.Val262Met, was not documented in the control sample in Taiwan BioBank. Immunoblotting revealed HSPA1Lp.Val262Met mutant with decreased protein expression in SH-SY5Y cells compared with the wild type. Conclusions: While common variants in the HSPA1A, HSPA1B, and HSPA1L genes do not seem to be significant genetic risk factors for schizophrenia in this cohort, the ultra-rare mutation, HSPA1Lp.Val262Met, significantly reduces protein expression. These preliminary findings suggest that a potential loss-of-function or reduced expression of the HSPA1L gene may be a predisposing factor contributing to schizophrenia vulnerability in certain individuals. However, the finding should be replicated in other independent samples. The in vitro and in vivo impacts of the associated mutation at the HSPA1L gene on the pathophysiology of schizophrenia are worthy of future investigation.<\/jats:p>","DOI":"10.3390\/genes17070727","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T14:27:52Z","timestamp":1783434472000},"page":"727","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Analysis of the HSPA1A, HSPA1B, and HSPA1L Genes in Patients with Schizophrenia from Taiwan"],"prefix":"10.3390","volume":"17","author":[{"given":"Ying-Chieh","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 98142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shih-Hsin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 98142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Yao","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 98142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2962-0911","authenticated-orcid":false,"given":"Min-Chih","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Yuli Branch, Taipei Veterans General Hospital, Hualien 98142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1016\/S0140-6736(15)01121-6","article-title":"Schizophrenia","volume":"388","author":"Owen","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1038\/mp.2014.148","article-title":"Schizophrenia genetics: Emerging themes for a complex disorder","volume":"20","author":"Kavanagh","year":"2015","journal-title":"Mol. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1038\/s41380-023-02043-w","article-title":"The synaptic hypothesis of schizophrenia version III: A master mechanism","volume":"28","author":"Howes","year":"2023","journal-title":"Mol. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1093\/schbul\/sby024","article-title":"Inflammation in schizophrenia: Pathogenetic aspects and therapeutic considerations","volume":"44","year":"2018","journal-title":"Schizophr. Bull."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3702","DOI":"10.1016\/j.febslet.2007.05.039","article-title":"The heat shock protein 70 family: Highly homologous proteins with overlapping and distinct functions","volume":"581","author":"Daugaard","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/S0163-7258(98)00028-X","article-title":"Heat shock protein 70 kDa: Molecular biology, biochemistry, and physiology","volume":"80","author":"Kiang","year":"1998","journal-title":"Pharmacol. Ther."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.neuroscience.2021.02.026","article-title":"A search for biomarkers of early-life stress-related psychopathology: Focus on 70-kDa heat shock proteins","volume":"463","author":"Solarz","year":"2021","journal-title":"Neuroscience"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1007\/s12192-016-0676-6","article-title":"The human HSP70 family of chaperones: Where do we stand?","volume":"21","author":"Radons","year":"2016","journal-title":"Cell Stress Chaperones"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/syn.10048","article-title":"Enhancement of presynaptic performance in transgenic Drosophila overexpressing heat shock protein Hsp70","volume":"44","author":"Karunanithi","year":"2002","journal-title":"Synapse"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1046\/j.1471-4159.2000.740641.x","article-title":"Localization of the heat-shock protein Hsp70 to the synapse following hyperthermic stress in the brain","volume":"74","author":"Bechtold","year":"2000","journal-title":"J. Neurochem."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Zatsepina, O.G., Evgen\u2019ev, M.B., and Garbuz, D.G. (2021). Role of a heat shock transcription factor and the major heat shock protein Hsp70 in memory formation and neuroprotection. Cells, 10.","DOI":"10.3390\/cells10071638"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/S0952-3278(96)90153-2","article-title":"Heat stress lipids and schizophrenia","volume":"55","author":"Bates","year":"1996","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1093\/schbul\/sbs087","article-title":"Evaluation of HLA polymorphisms in relation to schizophrenia risk and infectious exposure","volume":"38","author":"Bamne","year":"2012","journal-title":"Schizophr. Bull."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/ajmg.b.32195","article-title":"HLA associations in schizophrenia: Are we re-discovering the wheel?","volume":"165","author":"Kodavali","year":"2014","journal-title":"Am. J. Med. Genet. B Neuropsychiatr. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/S0920-9964(00)00091-8","article-title":"Identification of antibodies to heat shock proteins 90 kDa and 70 kDa in patients with schizophrenia","volume":"52","author":"Kim","year":"2001","journal-title":"Schizophr. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1176\/ajp.156.7.1103","article-title":"Antibodies to heat shock proteins in schizophrenic patients: Implications for the mechanism of the disease","volume":"156","author":"Schwarz","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1016\/j.arcmed.2018.10.002","article-title":"Association studies of HSPA1A and HSPA1L gene polymorphisms with schizophrenia","volume":"49","author":"Kowalczyk","year":"2018","journal-title":"Arch. Med. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/s00406-007-0791-6","article-title":"Association analysis of heat shock protein 70 gene polymorphisms in schizophrenia","volume":"258","author":"Kim","year":"2008","journal-title":"Eur. Arch. Psychiatry Clin. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/s12017-019-08575-1","article-title":"Association of HSPA1B polymorphisms with paranoid schizophrenia in a Polish population","volume":"22","author":"Kowalczyk","year":"2020","journal-title":"Neuromolecular Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1159\/000218075","article-title":"The impact of heat shock protein 70 gene variations on clinical presentation and outcome in schizophrenic inpatients","volume":"59","author":"Pae","year":"2009","journal-title":"Neuropsychobiology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.neures.2005.05.004","article-title":"Polymorphisms of heat shock protein 70 gene (HSPA1A, HSPA1B and HSPA1L) and schizophrenia","volume":"53","author":"Pae","year":"2005","journal-title":"Neurosci. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s12192-013-0446-7","article-title":"Heat shock protein 70 gene polymorphisms are associated with paranoid schizophrenia in the Polish population","volume":"19","author":"Kowalczyk","year":"2014","journal-title":"Cell Stress Chaperones"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/nature12975","article-title":"A polygenic burden of rare disruptive mutations in schizophrenia","volume":"506","author":"Purcell","year":"2014","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/nature12929","article-title":"De novo mutations in schizophrenia implicate synaptic networks","volume":"506","author":"Fromer","year":"2014","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Wang, Y.Y., Hsu, S.H., Tsai, H.Y., Cheng, F.Y., and Cheng, M.C. (2022). Transcriptomic and proteomic analysis of CRISPR\/Cas9-mediated ARC-knockout HEK293 cells. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094498"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1192\/bjp.bp.106.033761","article-title":"Phenotypic and genetic complexity of psychosis. Invited commentary on ... Schizophrenia: A common disease caused by multiple rare alleles","volume":"190","author":"Craddock","year":"2007","journal-title":"Br. J. Psychiatry"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1192\/bjp.bp.106.025585","article-title":"Schizophrenia: A common disease caused by multiple rare alleles","volume":"190","author":"McClellan","year":"2007","journal-title":"Br. J. Psychiatry"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.gde.2009.04.010","article-title":"Common vs. rare allele hypotheses for complex diseases","volume":"19","author":"Schork","year":"2009","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/nature08494","article-title":"Finding the missing heritability of complex diseases","volume":"461","author":"Manolio","year":"2009","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1016\/S0140-6736(03)12715-8","article-title":"Problems of reporting genetic associations with complex outcomes","volume":"361","author":"Colhoun","year":"2003","journal-title":"Lancet"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.mcn.2017.11.013","article-title":"Heat shock protein 70 suppresses neuroinflammation induced by \u03b1-synuclein in astrocytes","volume":"86","author":"Yu","year":"2018","journal-title":"Mol. Cell Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Wisniewska, M., Karlberg, T., Lehti\u00f6, L., Johansson, I., Kotenyova, T., Moche, M., and Sch\u00fcler, H. (2010). Crystal structures of the ATPase domains of four human Hsp70 isoforms: HSPA1L\/Hsp70-hom, HSPA2\/Hsp70-2, HSPA6\/Hsp70B\u2019, and HSPA5\/BiP\/GRP78. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0008625"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/727\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:06:15Z","timestamp":1783515975000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/727"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,23]]},"references-count":32,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["genes17070727"],"URL":"https:\/\/doi.org\/10.3390\/genes17070727","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,23]]}}}