{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T10:14:31Z","timestamp":1784110471230,"version":"3.55.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"3-4","license":[{"start":{"date-parts":[[2021,3,9]],"date-time":"2021-03-09T00:00:00Z","timestamp":1615248000000},"content-version":"vor","delay-in-days":36,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003407","name":"Ministero dell\u2019Istruzione, dell\u2019Universit\u00e0 e della Ricerca","doi-asserted-by":"publisher","award":["PRIN 2017WJZ9W9"],"award-info":[{"award-number":["PRIN 2017WJZ9W9"]}],"id":[{"id":"10.13039\/501100003407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Associazione Amici del Bambino Malato Onlus"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,4,26]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Mutations in the WFS1 gene, encoding wolframin (WFS1), cause endoplasmic reticulum (ER) stress and are associated with a rare autosomal-recessive disorder known as Wolfram syndrome (WS). WS is clinically characterized by childhood-onset diabetes mellitus, optic atrophy, deafness, diabetes insipidus and neurological signs. We identified two novel WFS1 mutations in a patient with WS, namely, c.316-1G\u2009&amp;gt;\u2009A (in intron 3) and c.757A\u2009&amp;gt;\u2009T (in exon 7). Both mutations, located in the N-terminal region of the protein, were predicted to generate a truncated and inactive form of WFS1. We found that although the WFS1 protein was not expressed in peripheral blood mononuclear cells (PBMCs) of the proband, no constitutive ER stress activation could be detected in those cells. In contrast, WS proband\u2019s PBMCs produced very high levels of proinflammatory cytokines (i.e. TNF-\u03b1, IL-1\u03b2, and IL-6) in the absence of any stimulus. WFS1 silencing in PBMCs from control subjects by means of small RNA interference also induced a pronounced proinflammatory cytokine profile. The same cytokines were also significantly higher in sera from the WS patient as compared to matched healthy controls. Moreover, the chronic inflammatory state was associated with a dominance of proinflammatory T helper 17 (Th17)-type cells over regulatory T (Treg) lymphocytes in the WS PBMCs. The identification of a state of systemic chronic inflammation associated with WFS1 deficiency may pave the way to innovative and personalized therapeutic interventions in WS.<\/jats:p>","DOI":"10.1093\/hmg\/ddab040","type":"journal-article","created":{"date-parts":[[2021,2,19]],"date-time":"2021-02-19T13:11:47Z","timestamp":1613740307000},"page":"265-276","source":"Crossref","is-referenced-by-count":36,"title":["Novel mutations in the <i>WFS1<\/i> gene are associated with Wolfram syndrome and systemic inflammation"],"prefix":"10.1093","volume":"30","author":[{"given":"Eleonora","family":"Panfili","sequence":"first","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giada","family":"Mondanelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciriana","family":"Orabona","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria L","family":"Belladonna","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Gargaro","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Fallarino","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Orecchini","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Prontera","sequence":"additional","affiliation":[{"name":"Medical Genetics Unit, University-Hospital \u201cSanta Maria della Misericordia\u201d, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Proietti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulio","family":"Frontino","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, 20132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Tirelli","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Diabetes Research Institute, IRCCS San Raffaele Hospital, Milan, 20132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberta","family":"Iacono","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"Vacca","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Puccetti","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Grohmann","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"},{"name":"Visiting Professor, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanna","family":"Esposito","sequence":"additional","affiliation":[{"name":"Pediatric Clinic Pietro Barilla Children\u2019s Hospital, Department of Medicine and Surgery, Universit\u00e0 di Parma, Parma, 43126, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria T","family":"Pallotta","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Perugia, Perugia, 06132, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"2021050309130883400_ref1","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s12967-019-1993-1","article-title":"Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives","volume":"17","author":"Pallotta","year":"2019","journal-title":"J. Transl. Med."},{"key":"2021050309130883400_ref2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1007\/s11892-015-0702-6","article-title":"Wolfram syndrome: diagnosis, management, and treatment","volume":"16","author":"Urano","year":"2016","journal-title":"Curr. Diab. Rep."},{"key":"2021050309130883400_ref3","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1038\/pr.2018.17","article-title":"Genetic and clinical aspects of Wolfram syndrome 1, a severe neurodegenerative disease","volume":"83","author":"Rigoli","year":"2018","journal-title":"Pediatr. Res."},{"key":"2021050309130883400_ref4","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1136\/jmg.34.10.838","article-title":"Wolfram (DIDMOAD) syndrome","volume":"34","author":"Barrett","year":"1997","journal-title":"J. Med. Genet."},{"key":"2021050309130883400_ref5","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/2441","article-title":"A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome)","volume":"20","author":"Inoue","year":"1998","journal-title":"Nat. Genet."},{"key":"2021050309130883400_ref6","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1093\/hmg\/7.13.2021","article-title":"Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein","volume":"7","author":"Strom","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"2021050309130883400_ref7","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1172\/JCI39678","article-title":"Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells","volume":"120","author":"Fonseca","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2021050309130883400_ref8","doi-asserted-by":"crossref","first-page":"39609","DOI":"10.1074\/jbc.M507426200","article-title":"WFS1 is a novel component of the unfolded protein response and maintains homeostasis of the endoplasmic reticulum in pancreatic beta-cells","volume":"280","author":"Fonseca","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021050309130883400_ref9","doi-asserted-by":"crossref","first-page":"382","DOI":"10.3390\/ijms18020382","article-title":"Endoplasmic reticulum (ER) stress and endocrine disorders","volume":"18","author":"Ariyasu","year":"2017","journal-title":"Int. J. Mol. Sci."},{"key":"2021050309130883400_ref10","first-page":"9412676","article-title":"Wolfram syndrome: a case report and review of clinical manifestations, genetics pathophysiology, and potential therapies","volume":"2018","author":"Toppings","year":"2018","journal-title":"Case Rep Endocrinol"},{"key":"2021050309130883400_ref11","first-page":"705","article-title":"Roles of endoplasmic reticulum stress in immune responses","volume":"41","author":"So","year":"2018","journal-title":"Mol. Cells"},{"key":"2021050309130883400_ref12","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nature07203","article-title":"From endoplasmic-reticulum stress to the inflammatory response","volume":"454","author":"Zhang","year":"2008","journal-title":"Nature"},{"key":"2021050309130883400_ref13","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1038\/icb.2011.112","article-title":"The interplay between endoplasmic reticulum stress and inflammation","volume":"90","author":"Hasnain","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"2021050309130883400_ref14","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1530\/eje.1.01945","article-title":"Endoplasmic reticulum stress induces Wfs1 gene expression in pancreatic beta-cells via transcriptional activation","volume":"153","author":"Ueda","year":"2005","journal-title":"Eur. J. Endocrinol."},{"key":"2021050309130883400_ref15","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.bbrc.2004.10.017","article-title":"Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein","volume":"325","author":"Yamaguchi","year":"2004","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2021050309130883400_ref16","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1186\/s13000-019-0891-4","article-title":"Treg\/Th17 imbalance and its clinical significance in patients with hepatitis B-associated liver cirrhosis","volume":"14","author":"Lan","year":"2019","journal-title":"Diagn. Pathol."},{"key":"2021050309130883400_ref17","doi-asserted-by":"crossref","first-page":"40414","DOI":"10.1038\/srep40414","article-title":"Imbalance of Th17\/Treg cells in pathogenesis of patients with human leukocyte antigen B27 associated acute anterior uveitis","volume":"7","author":"Zhuang","year":"2017","journal-title":"Sci. Rep."},{"key":"2021050309130883400_ref18","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1007\/s00296-010-1710-0","article-title":"The Th17\/Treg imbalance and cytokine environment in peripheral blood of patients with rheumatoid arthritis","volume":"32","author":"Wang","year":"2012","journal-title":"Rheumatol. Int."},{"key":"2021050309130883400_ref19","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.cell.2010.02.021","article-title":"Th17 and regulatory T cells in mediating and restraining inflammation","volume":"140","author":"Littman","year":"2010","journal-title":"Cell"},{"key":"2021050309130883400_ref20","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.1007\/s00018-009-0248-3","article-title":"T helper 17 cells: discovery, function, and physiological trigger","volume":"67","author":"Torchinsky","year":"2010","journal-title":"Cell. Mol. Life Sci."},{"key":"2021050309130883400_ref21","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1158\/2326-6066.CIR-16-0193","article-title":"Regulatory T cells: differentiation and function","volume":"4","author":"Plitas","year":"2016","journal-title":"Cancer Immunol. Res."},{"key":"2021050309130883400_ref22","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.cell.2006.07.035","article-title":"The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells","volume":"126","author":"Ivanov","year":"2006","journal-title":"Cell"},{"key":"2021050309130883400_ref23","doi-asserted-by":"crossref","first-page":"179","DOI":"10.4049\/jimmunol.178.1.179","article-title":"Th3 cells in peripheral tolerance. I. Induction of Foxp3-positive regulatory T cells by Th3 cells derived from TGF-beta T cell-transgenic mice","volume":"178","author":"Carrier","year":"2007","journal-title":"J. Immunol."},{"key":"2021050309130883400_ref24","doi-asserted-by":"crossref","first-page":"1407","DOI":"10.2337\/diabetes.54.5.1407","article-title":"Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes","volume":"54","author":"Brusko","year":"2005","journal-title":"Diabetes"},{"key":"2021050309130883400_ref25","doi-asserted-by":"crossref","first-page":"407","DOI":"10.2337\/db09-0694","article-title":"Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects","volume":"59","author":"Long","year":"2010","journal-title":"Diabetes"},{"key":"2021050309130883400_ref26","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1084\/jem.20031579","article-title":"Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis","volume":"199","author":"Viglietta","year":"2004","journal-title":"J. Exp. Med."},{"key":"2021050309130883400_ref27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/978-0-387-72005-0_12","article-title":"Reduced number and function of CD4+CD25highFoxP3+ regulatory T cells in patients with systemic lupus erythematosus","volume":"601","author":"Lyssuk","year":"2007","journal-title":"Adv. Exp. Med. Biol."},{"key":"2021050309130883400_ref28","doi-asserted-by":"crossref","first-page":"e146","DOI":"10.1371\/journal.pone.0000146","article-title":"At-risk and recent-onset type 1 diabetic subjects have increased apoptosis in the CD4+CD25+ T-cell fraction","volume":"2","author":"Glisic-Milosavljevic","year":"2007","journal-title":"PLoS One"},{"key":"2021050309130883400_ref29","doi-asserted-by":"crossref","first-page":"3815","DOI":"10.1093\/hmg\/ddz212","article-title":"Functional assessment of variants associated with Wolfram syndrome","volume":"28","author":"Riachi","year":"2019","journal-title":"Hum. Mol. Genet."},{"key":"2021050309130883400_ref30","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/s41390-019-0487-4","article-title":"Wolfram syndrome 1 in the Italian population: genotype-phenotype correlations","volume":"87","author":"Rigoli","year":"2020","journal-title":"Pediatr. Res."},{"key":"2021050309130883400_ref31","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1038\/gim.2012.180","article-title":"Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype","volume":"15","author":"Heredia","year":"2013","journal-title":"Genet. Med."},{"key":"2021050309130883400_ref32","first-page":"11497","article-title":"The changing paradigm of intron retention: regulation, ramifications and recipes","volume":"47","author":"Monteuuis","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2021050309130883400_ref33","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1210\/er.2002-0018","article-title":"When translation meets metabolism: multiple links to diabetes","volume":"24","author":"Shi","year":"2003","journal-title":"Endocr. Rev."},{"key":"2021050309130883400_ref34","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1016\/j.cmet.2012.07.005","article-title":"Thioredoxin-interacting protein mediates ER stress-induced \u03b2 cell death through initiation of the inflammasome","volume":"16","author":"Oslowski","year":"2012","journal-title":"Cell Metab."},{"key":"2021050309130883400_ref35","doi-asserted-by":"crossref","first-page":"5611","DOI":"10.1038\/s41598-017-05935-4","article-title":"Targeting cellular calcium homeostasis to prevent cytokine-mediated Beta cell death","volume":"7","author":"Clark","year":"2017","journal-title":"Sci. Rep."},{"key":"2021050309130883400_ref36","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.immuni.2004.12.012","article-title":"VDUP1 is required for the development of natural killer cells","volume":"22","author":"Lee","year":"2005","journal-title":"Immunity"},{"key":"2021050309130883400_ref37","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1002\/eji.200737939","article-title":"Dendritic cells derived from TBP-2-deficient mice are defective in inducing T cell responses","volume":"38","author":"Son","year":"2008","journal-title":"Eur. J. Immunol."},{"key":"2021050309130883400_ref38","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/sji.12404","article-title":"Characterization of Th17 and FoxP3(+) Treg cells in paediatric psoriasis patients","volume":"83","author":"Zhang","year":"2016","journal-title":"Scand. J. Immunol."},{"key":"2021050309130883400_ref39","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1056\/NEJMra0707449","article-title":"Interleukin-17 and type 17 helper T cells","volume":"361","author":"Miossec","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"2021050309130883400_ref40","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1002\/art.23291","article-title":"Interleukin-17-producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers","volume":"58","author":"Nistala","year":"2008","journal-title":"Arthritis Rheum."},{"key":"2021050309130883400_ref41","doi-asserted-by":"crossref","first-page":"146","DOI":"10.2353\/ajpath.2008.070690","article-title":"Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis","volume":"172","author":"Tzartos","year":"2008","journal-title":"Am. J. Pathol."},{"key":"2021050309130883400_ref42","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1038\/ni1497","article-title":"Development, cytokine profile and function of human interleukin 17-producing helper T cells","volume":"8","author":"Wilson","year":"2007","journal-title":"Nat. Immunol."},{"key":"2021050309130883400_ref43","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.1038\/s41419-017-0010-y","article-title":"Increased apoptosis of regulatory T cells in patients with active autoimmune hepatitis","volume":"8","author":"John","year":"2017","journal-title":"Cell Death Dis."},{"key":"2021050309130883400_ref44","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1196\/annals.1361.095","article-title":"Increased spontaneous apoptosis of CD4+CD25+ T cells in patients with active rheumatoid arthritis is reduced by infliximab","volume":"1051","author":"Toubi","year":"2005","journal-title":"Ann. N.Y. Acad. Sci."},{"key":"2021050309130883400_ref45","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1186\/s12967-019-1948-6","article-title":"The clinical value of cytokines in chronic fatigue syndrome","volume":"17","author":"Yang","year":"2019","journal-title":"J. Transl. Med."},{"key":"2021050309130883400_ref46","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1016\/j.neubiorev.2020.09.011","article-title":"Function of WFS1 and WFS2 in the central nervous system: implications for Wolfram syndrome and Alzheimer's disease","volume":"118","author":"Li","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"2021050309130883400_ref47","doi-asserted-by":"crossref","first-page":"e1007196","DOI":"10.1371\/journal.pgen.1007196","article-title":"Knockdown of wfs1, a fly homolog of Wolfram syndrome 1, in the nervous system increases susceptibility to age- and stress-induced neuronal dysfunction and degeneration in drosophila","volume":"14","author":"Sakakibara","year":"2018","journal-title":"PLoS Genet."},{"key":"2021050309130883400_ref48","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.neulet.2006.06.066","article-title":"Association study of sporadic Parkinson's disease genetic risk factors in patients from Russia by APEX technology","volume":"405","author":"Shadrina","year":"2006","journal-title":"Neurosci. Lett."},{"key":"2021050309130883400_ref49","doi-asserted-by":"crossref","first-page":"70","DOI":"10.9758\/cpn.2017.15.1.70","article-title":"Mania in Wolfram's disease: from bedside to bench","volume":"15","author":"Chatterjee","year":"2017","journal-title":"Clin Psychopharmacol Neurosci"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab040\/36860438\/ddab040.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/3-4\/265\/37771905\/ddab040.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/3-4\/265\/37771905\/ddab040.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,5,3]],"date-time":"2021-05-03T09:13:33Z","timestamp":1620033213000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/30\/3-4\/265\/6159699"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,1]]},"references-count":49,"journal-issue":{"issue":"3-4","published-online":{"date-parts":[[2021,3,9]]},"published-print":{"date-parts":[[2021,4,26]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab040","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,2,1]]},"published":{"date-parts":[[2021,2,1]]}}}