{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:29:06Z","timestamp":1760146146440,"version":"build-2065373602"},"reference-count":62,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,12]],"date-time":"2024-10-12T00:00:00Z","timestamp":1728691200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Italian Ministry of Health with \u201ccurrent research funds\u201d"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Autoimmune polyglandular syndrome (APS) comprises a complex association of autoimmune pathological conditions. APS Type 1 originates from loss-of-function mutations in the autoimmune regulator (AIRE) gene. APS2, APS3 and APS4 are linked to specific HLA alleles within the major histocompatibility complex, with single-nucleotide polymorphisms (SNPs) in non-HLA genes also contributing to disease. In general, variability in the AIRE locus and the presence of heterozygous loss-of-function mutations can impact self-antigen presentation in the thymus. In this study, whole-exome sequencing (WES) was performed on a sixteen-year-old female APS3A\/B patient to investigate the genetic basis of her complex phenotype. The analysis identified two variants (p.Arg111Trp and p.Thr101Ile) of the hepatitis A virus cell receptor 2 gene (HAVCR2) encoding for the TIM-3 (T cell immunoglobulin and mucin domain 3) protein. These variants were predicted, through in silico analysis, to impact protein structure and stability, potentially influencing the patient\u2019s autoimmune phenotype. While confocal microscopy analysis revealed no alteration in TIM-3 fluorescence intensity between the PBMCs isolated from the patient and those of a healthy donor, RT-qPCR showed reduced TIM-3 expression in the patient\u2019s unfractionated PBMCs. A screening conducted on a cohort of thirty APS patients indicated that the p.Thr101Ile and p.Arg111Trp mutations were unique to the proband. This study opens the pathway for the search of TIM-3 variants possibly linked to complex autoimmune phenotypes, highlighting the potential of novel variant discovery in contributing to APS classification and diagnosis.<\/jats:p>","DOI":"10.3390\/ijms252010994","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T04:02:58Z","timestamp":1728878578000},"page":"10994","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Putative Role of TIM-3 Variants in Polyendocrine Autoimmunity: Insights from a WES Investigation"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9967-1290","authenticated-orcid":false,"given":"Andrea","family":"Ariolli","sequence":"first","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6543-6225","authenticated-orcid":false,"given":"Emanuele","family":"Agolini","sequence":"additional","affiliation":[{"name":"Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0434-8533","authenticated-orcid":false,"given":"Tommaso","family":"Mazza","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"},{"name":"Laboratory of Bioinformatics, Casa Sollievo della Sofferenza, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 70013 San Giovanni Rotondo, Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9478-7929","authenticated-orcid":false,"given":"Francesco","family":"Petrizzelli","sequence":"additional","affiliation":[{"name":"Laboratory of Bioinformatics, Casa Sollievo della Sofferenza, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 70013 San Giovanni Rotondo, Foggia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3249-0003","authenticated-orcid":false,"given":"Stefania","family":"Petrini","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Core Facility, Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentina","family":"D\u2019Oria","sequence":"additional","affiliation":[{"name":"Confocal Microscopy Core Facility, Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Annamaria","family":"Cudini","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Caterina","family":"Nardella","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanessa","family":"Pesce","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donatella","family":"Comparcola","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5647-7519","authenticated-orcid":false,"given":"Marco","family":"Cappa","sequence":"additional","affiliation":[{"name":"Research Unit Innovative Therapies for Endocrinopathies, Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3078-9754","authenticated-orcid":false,"given":"Alessandra","family":"Fierabracci","sequence":"additional","affiliation":[{"name":"Bambino Ges\u00f9 Children\u2019s Hospital, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 00146 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Colao, A., Jaffrain-Rea, M.-L., and Beckers, A. (2019). Autoimmune Polyendocrine Syndromes (APS) or Multiple Autoimmune Syndromes (MAS). Polyendocrine Disorders and Endocrine Neoplastic Syndromes, Springer International Publishing.","DOI":"10.1007\/978-3-319-73082-0"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1007\/s40618-022-01994-1","article-title":"Type 3 autoimmune polyglandular syndrome (APS-3) or type 3 multiple autoimmune syndrome (MAS-3): An expanding galaxy","volume":"46","author":"Betterle","year":"2023","journal-title":"J. Endocrinol. Investig."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cudini, A., Nardella, C., Bellacchio, E., Palma, A., Delfino, D.V., Betterle, C., Cappa, M., and Fierabracci, A. (2024). Analysis of the AIRE Gene Promoter in Patients Affected by Autoimmune Polyendocrine Syndromes. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25052656"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Fierabracci, A. (2016). Type 1 Diabetes in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome (APECED): A \u201cRare\u201d Manifestation in a \u201cRare\u201d Disease. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17071106"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4769","DOI":"10.1210\/jc.2019-00602","article-title":"Autoimmune Polyendocrinopathy","volume":"104","author":"Frommer","year":"2019","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1056\/NEJMra1510030","article-title":"Graves\u2019 Disease","volume":"375","author":"Smith","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"102649","DOI":"10.1016\/j.autrev.2020.102649","article-title":"Hashimoto\u2019s thyroiditis: An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation","volume":"19","author":"Ralli","year":"2020","journal-title":"Autoimmun. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.autrev.2012.12.003","article-title":"The putative role of the C1858T polymorphism of protein tyrosine phosphatase PTPN22 gene in autoimmunity","volume":"12","author":"Gianchecchi","year":"2013","journal-title":"Autoimmun. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1038\/ng1673","article-title":"Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant","volume":"37","author":"Vang","year":"2005","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1977","DOI":"10.1210\/jc.2017-02577","article-title":"PTPN22 and CTLA-4 Polymorphisms Are Associated With Polyglandular Autoimmunity","volume":"103","author":"Houcken","year":"2018","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1007\/s00125-013-3113-8","article-title":"Plasma concentrations of soluble IL-2 receptor \u03b1 (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients","volume":"57","author":"Downes","year":"2014","journal-title":"Diabetologia"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Khan, S., Mandal, R.K., Jawed, A., Dar, S.A., Wahid, M., Panda, A.K., Areeshi, M.Y., Ahmed Khan, M.E., and Haque, S. (2016). TNF-\u03b1 -308 G\u2009>\u2009A (rs1800629) Polymorphism is Associated with Celiac Disease: A Meta-analysis of 11 Case-Control Studies. Sci. Rep., 6.","DOI":"10.1038\/srep32677"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1080\/08820130902766092","article-title":"The Proinflammatory Cytokine TNF-\u03b1 -308 AA Genotype is Associated with Polyglandular Autoimmunity","volume":"38","author":"Dittmar","year":"2009","journal-title":"Immunol. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Grover, P., Goel, P.N., and Greene, M.I. (2021). Regulatory T Cells: Regulation of Identity and Function. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.750542"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1126\/science.285.5428.727","article-title":"Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA","volume":"285","author":"Bauer","year":"1999","journal-title":"Science"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/s00063-007-1001-z","article-title":"Polymorphisms of MICA microsatellites in thyroidal autoimmunity","volume":"102","author":"Ide","year":"2007","journal-title":"Med. Klin."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1089\/thy.2008.1565","article-title":"Type 1 diabetes and autoimmune thyroiditis: The genetic connection","volume":"19","author":"Tomer","year":"2009","journal-title":"Thyroid"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1089\/thy.2005.15.239","article-title":"Immunoregulatory and susceptibility genes in thyroid and polyglandular autoimmunity","volume":"15","author":"Dittmar","year":"2005","journal-title":"Thyroid"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.coi.2016.07.003","article-title":"AIRE-mutations and autoimmune disease","volume":"43","author":"Bruserud","year":"2016","journal-title":"Curr. Opin. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/s41467-021-21015-8","article-title":"GWAS for autoimmune Addison\u2019s disease identifies multiple risk loci and highlights AIRE in disease susceptibility","volume":"12","author":"Eriksson","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"106818","DOI":"10.1016\/j.isci.2023.106818","article-title":"Dominant-negative heterozygous mutations in AIRE confer diverse autoimmune phenotypes","volume":"26","author":"Oftedal","year":"2023","journal-title":"iScience"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1016\/j.immuni.2015.04.021","article-title":"Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases","volume":"42","author":"Oftedal","year":"2015","journal-title":"Immunity"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/gim.2015.148","article-title":"Clinical application of whole-exome sequencing across clinical indications","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/415536a","article-title":"Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease","volume":"415","author":"Monney","year":"2002","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2743","DOI":"10.3324\/haematol.2022.282419","article-title":"Germline HAVCR2 mutations and their relation to the clinical spectrum of subcutaneous panniculitis-like T-cell lymphoma and hemophagocytic lymphohistiocytosis: Results from a multicenter study and meta-analysis","volume":"108","author":"Moonla","year":"2023","journal-title":"Haematologica"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.4049\/jimmunol.0903059","article-title":"T cell\/transmembrane, Ig, and mucin-3 allelic variants differentially recognize phosphatidylserine and mediate phagocytosis of apoptotic cells","volume":"184","author":"DeKruyff","year":"2010","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4501","DOI":"10.1182\/bloodadvances.2022007450","article-title":"Treatment of an HLH-mimic disease based on HAVCR2 variants with absent TIM-3 expression","volume":"6","author":"Tromp","year":"2022","journal-title":"Blood Adv."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Fierabracci, A., Belcastro, E., Carbone, E., Pagliarosi, O., Palma, A., Pacillo, L., Giancotta, C., Zangari, P., Finocchi, A., and Cancrini, C. (2022). In Search for the Missing Link in APECED-like Conditions: Analysis of the AIRE Gene in a Series of 48 Patients. J. Clin. Med., 11.","DOI":"10.3390\/jcm11113242"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107933","DOI":"10.1016\/j.intimp.2021.107933","article-title":"TIM-3: An update on immunotherapy","volume":"99","author":"Zhao","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1111\/j.0105-2896.2010.00903.x","article-title":"TIM genes: A family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity","volume":"235","author":"Freeman","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3821","DOI":"10.1182\/blood-2008-10-185884","article-title":"Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation","volume":"113","author":"Nakayama","year":"2009","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1038\/ni.2396","article-title":"Tumor immunity times out: TIM-3 and HMGB1","volume":"13","author":"Tang","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nature17421","article-title":"Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion","volume":"536","author":"Huang","year":"2016","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1126\/science.1148536","article-title":"Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells","volume":"318","author":"Anderson","year":"2007","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1002\/eji.200939274","article-title":"TIM-3 is expressed on activated human CD4+ T cells and regulates Th1 and Th17 cytokines","volume":"39","author":"Hastings","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"989","DOI":"10.1016\/j.immuni.2016.05.001","article-title":"Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation","volume":"44","author":"Anderson","year":"2016","journal-title":"Immunity"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1889822","DOI":"10.1080\/2162402X.2021.1889822","article-title":"TIM-3 levels correlate with enhanced NK cell cytotoxicity and improved clinical outcome in AML patients","volume":"10","author":"Rakova","year":"2021","journal-title":"Oncoimmunology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1038\/ni987","article-title":"Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance","volume":"4","author":"Tian","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1111\/j.1744-313X.2011.01046.x","article-title":"The -1541 C>T and +4259 G>T of TIM-3 polymorphisms are associated with rheumatoid arthritis susceptibility in a Chinese Hui population","volume":"38","author":"Xu","year":"2011","journal-title":"Int. J. Immunogenet."},{"key":"ref_40","first-page":"644","article-title":"TIM-3 Rs10515746 (A\/C) and Rs10053538 (C\/A) Gene Polymorphisms and Risk of Multiple Sclerosis","volume":"45","author":"Yaghoobi","year":"2016","journal-title":"Iran. J. Public Health"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1007\/s10238-013-0264-3","article-title":"Expression of human T cell immunoglobulin domain and mucin-3 (TIM-3) on kidney tissue from systemic lupus erythematosus (SLE) patients","volume":"14","author":"Guo","year":"2014","journal-title":"Clin. Exp. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1084\/jem.20060210","article-title":"Dysregulated T cell expression of TIM3 in multiple sclerosis","volume":"203","author":"Koguchi","year":"2006","journal-title":"J. Exp. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"701","DOI":"10.3109\/00365521.2011.568518","article-title":"Dysregulated upregulation of T-cell immunoglobulin and mucin domain-3 on mucosal T helper 1 cells in patients with Crohn\u2019s disease","volume":"46","author":"Morimoto","year":"2011","journal-title":"Scand. J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1016\/j.clim.2012.09.001","article-title":"Dysregulated Tim-3 expression and its correlation with imbalanced CD4 helper T cell function in ulcerative colitis","volume":"145","author":"Shi","year":"2012","journal-title":"Clin. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Liu, Y., Chen, Z., Xiao, Y., Chen, H., and Zhou, Z. (2022). Altered expression of Tim family molecules and an imbalanced ratio of Tim-3 to Tim-1 expression in patients with type 1 diabetes. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.937109"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Boehne, C., Behrendt, A.K., Meyer-Bahlburg, A., Boettcher, M., Drube, S., Kamradt, T., and Hansen, G. (2021). Tim-3 is dispensable for allergic inflammation and respiratory tolerance in experimental asthma. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0249605"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1542\/pir.2020-004564","article-title":"Patent Ductus Arteriosus","volume":"42","author":"Eilers","year":"2021","journal-title":"Pediatr. Rev."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3928\/0090-4481-19800401-07","article-title":"Autoimmune polyglandular syndromes","volume":"9","author":"Neufeld","year":"1980","journal-title":"Pediatr. Ann."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1056\/NEJMra1713301","article-title":"Autoimmune Polyendocrine Syndromes","volume":"378","author":"Husebye","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.ygeno.2013.04.016","article-title":"Analysis of the autoimmune regulator gene in patients with autoimmune non-APECED polyendocrinopathies","volume":"102","author":"Palma","year":"2013","journal-title":"Genomics"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Arena, A., Belcastro, E., Ceccacci, F., Petrini, S., Conti, L.A., Pagliarosi, O., Giorda, E., Sennato, S., Schiaffini, R., and Wang, P. (2022). Improvement of Lipoplexes With a Sialic Acid Mimetic to Target the C1858T PTPN22 Variant for Immunotherapy in Endocrine Autoimmunity. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.838331"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1038\/nprot.2009.86","article-title":"Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm","volume":"4","author":"Kumar","year":"2009","journal-title":"Nat. Protoc."},{"key":"ref_54","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_55","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_56","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_57","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/j.jmb.2019.04.009","article-title":"Can Predicted Protein 3D Structures Provide Reliable Insights into whether Missense Variants Are Disease Associated?","volume":"431","author":"Ittisoponpisan","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"W382","DOI":"10.1093\/nar\/gki387","article-title":"The FoldX web server: An online force field","volume":"33","author":"Schymkowitz","year":"2005","journal-title":"Nucleic Acids Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1093\/bib\/bbx006","article-title":"Molecular dynamics recipes for genome research","volume":"19","author":"Biagini","year":"2017","journal-title":"Brief. Bioinform."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Cocciadiferro, D., Mazza, T., Vecchio, D., Biagini, T., Petrizzelli, F., Agolini, E., Villani, A., Minervino, D., Martinelli, D., and Rizzo, C. (2023). Exploiting in silico structural analysis to introduce emerging genotype-phenotype correlations in DHCR24-related sterol biosynthesis disorder: A case study. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.1307934"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Biagini, T., Petrizzelli, F., Truglio, M., Cespa, R., Barbieri, A., Capocefalo, D., Castellana, S., Tevy, M.F., Carella, M., and Mazza, T. (2019). Are Gaming-Enabled Graphic Processing Unit Cards Convenient for Molecular Dynamics Simulation?. Evol. Bioinform. Online, 15.","DOI":"10.1177\/1176934319850144"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"e4446","DOI":"10.1002\/pro.4446","article-title":"CHARMM-GUI Enhanced Sampler for various collective variables and enhanced sampling methods","volume":"31","author":"Suh","year":"2022","journal-title":"Protein Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/10994\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:12:14Z","timestamp":1760112734000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/20\/10994"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,12]]},"references-count":62,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2024,10]]}},"alternative-id":["ijms252010994"],"URL":"https:\/\/doi.org\/10.3390\/ijms252010994","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2024,10,12]]}}}