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Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>M\u00e9ni\u00e8re's disease (MD) is an inner ear disorder characterised by tinnitus, sensorineural hearing loss and dizziness, although around 60% of patients also exhibit and immune dysregulation. Transcriptomic studies have identified three distinct immune phenotypes in MD, classified based on systemic inflammation, cytokine profiles and association to autoinflammatory\/autoimmune comorbidities. Furthermore, genetic studies have shown aggregation of rare variants in MD patients; however, the relationship between genetic factors and immune responses remains poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we analysed exome data pertaining to NF-\u03baB pathway genes to identify ultrarare variants that could contribute to the immune phenotypes observed in MD. Furthermore, we retrieved MD epigenetic and transcriptomic data to search for the associated molecular signature. We performed protein modelling and receptor-ligand docking, as well as differential transcript usage (DTU) and splicing prediction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified ultrarare heterozygous variants in\n                      <jats:italic>TLR9<\/jats:italic>\n                      (chr3:52222299 G&amp;gt;C and chr3:52223761 C&amp;gt;A),\n                      <jats:italic>TNFRSF1B<\/jats:italic>\n                      (chr1:12167150 C&amp;gt;T and chr1:12202100 G&amp;gt;A), and FAS (chr10:89003139 G&amp;gt;A and chr10:89008919 C&amp;gt;T) in MD patients. Splicing predictions suggested potential creation of cryptic donor\/acceptor sites for\n                      <jats:italic>TLR9<\/jats:italic>\n                      and\n                      <jats:italic>TNFRSF1B<\/jats:italic>\n                      variants. Protein modelling predicted destabilising effects for all three proteins, with altered atomic interactions in\n                      <jats:italic>TNFRSF1B<\/jats:italic>\n                      and\n                      <jats:italic>FAS<\/jats:italic>\n                      . When docked, the\n                      <jats:italic>TLR9-TLR9<\/jats:italic>\n                      dimer and\n                      <jats:italic>FAS-FASGL<\/jats:italic>\n                      models, redistributed interfacial contacts, potentially reducing binding efficiency, whereas docked\n                      <jats:italic>TNFRSF1B-TRAF2<\/jats:italic>\n                      interactions were partially maintained.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings suggest that MD distinct immune phenotypes based on systemic inflammation and may be linked to comorbid autoimmune\/autoinflammatory disorders, with rare variants in\n                      <jats:italic>TLR9<\/jats:italic>\n                      ,\n                      <jats:italic>TNFRSF1B<\/jats:italic>\n                      and\n                      <jats:italic>FAS<\/jats:italic>\n                      likely contributing to autoinflammation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1789753","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T04:27:38Z","timestamp":1778819258000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Burden of novel and ultra-rare missense variants in the NF-\u03baB pathway genes associated to M\u00e9ni\u00e8re\u2019s disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Pablo","family":"Cruz-Granados","sequence":"first","affiliation":[{"name":"Meniere Disease Neuroscience Research Program, Faculty of Medicine & Health, School of Medical Sciences, The Kolling Institute, University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Rivero de Jesus","sequence":"additional","affiliation":[{"name":"Division de Otoneurologia, Department of Otorhinolaryngology, Consorci Sanitari Integral Moises Broggi Hospital, University of Barcelona","place":["Barcelona, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andres","family":"Soto-Varela","sequence":"additional","affiliation":[{"name":"Division of Neurotology, Department of Otorhinolaryngology, Complexo Hospitalario Universitario de Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"Department of Surgery and Medical-Surgical Specialities, School of Medicine, Universidade de Santiago de Compostela","place":["Santiago de Compostela, Spain"]},{"name":"Health Research Institute of Santiago (IDIS)","place":["Santiago de Compostela, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rocio","family":"Gonzalez-Aguado","sequence":"additional","affiliation":[{"name":"ENT Department. 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