{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:06:15Z","timestamp":1789506375368,"version":"build-2803163510"},"reference-count":177,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T00:00:00Z","timestamp":1776816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Systemic autoinflammatory diseases (SAIDs) are a rare, heterogeneous group of disorders caused by dysregulated innate immune activation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      To characterize the phenotype and clinical features of two unrelated cases with SAID suspicion, each carrying a heterozygous\n                      <jats:italic>NLRP12<\/jats:italic>\n                      variant of uncertain significance (VUS)\u2014one previously reported and one newly identified in Europeans\u2014and to evaluate their functional and genetic relevance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We analyzed clinical and genetic findings from two individuals harboring distinct heterozygous\n                      <jats:italic>NLRP12<\/jats:italic>\n                      variants not associated with Familial Cold Autoinflammatory Syndrome type 2 (FCAS2). Functional assays using peripheral blood mononuclear cells (PBMCs) were performed to assess the impact of these variants on cytokine production. Clinical features were compared among affected and unaffected family members and correlated with molecular findings.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Genetic screening revealed two different single nucleotide variants (SNVs) in\n                      <jats:italic>NLRP12<\/jats:italic>\n                      gene. The first, c.2854G&amp;gt;A (p.Asp952Asn), previously reported but still classified as a VUS, substitutes a negatively charged aspartic acid with an uncharged asparagine at residue 952. Structural modeling suggested disruption of local interactions between the pyrin domain (PYD) and leucine-rich repeat (LRR) domains, potentially impairing protein activation. The second variant, c.616C&amp;gt;G (p.Arg206Gly), represents a novel finding in Europeans, replacing a large positively charged arginine with a small, flexible glycine at residue 206. Modeling predicted destabilization of a loop near the nucleotide oligomerization core domain (NACHT) and loss of key interactions. Despite their classification as VUS according to the American College of Medical Genetics and Genomics (ACMG) criteria, both variants demonstrated functional impact. Carriers of p.Asp952Asn (index case, mother, and sibling) showed a marked, generalized increase in proinflammatory cytokines, particularly IL-1\u03b2, TNF-\u03b1, and IL-17A. The index case exhibited exceptionally high basal IL-1\u03b2 levels, consistent with an activated inflammatory state, and clinical data confirmed elevated C-reactive protein (CRP) levels. In contrast, the individual carrying p.Arg206Gly displayed a selective inflammatory response characterized by increases in IL-1\u03b2 and TNF-\u03b1 only after lipopolysaccharide (LPS) stimulation, not after muramyl dipeptide (MDP), with no elevation in IL-10 or IL-17A.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Functional data support that both\n                      <jats:italic>NLRP12<\/jats:italic>\n                      variants affect inflammatory cytokine production, though with distinct patterns: p.Asp952Asn induces broad hyperinflammation, whereas p.Arg206Gly results in stimulus-specific dysregulation. These findings highlight the importance of integrating genetic, structural, and functional evidence for the interpretation of\n                      <jats:italic>NLRP12<\/jats:italic>\n                      VUS in the context of Human Inborn Errors of Immunity and primary immunodeficiencies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1755711","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T04:40:37Z","timestamp":1776832837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinical description, genetic analysis and characterization of two NLRP12 heterozygous VUS variants"],"prefix":"10.3389","volume":"17","author":[{"given":"Asier","family":"Lizama-Mu\u00f1oz","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Molecular Biology and Immunology III, Faculty of Medicine, University of Granada","place":["Granada, Spain"]},{"name":"Clinical Analysis and Immunology Department, University Hospital Virgen de las Nieves","place":["Granada, Spain"]},{"name":"Institute for Biosanitary Research of Granada (ibs.GRANADA)","place":["Granada, Spain"]},{"name":"Programa de Doctorado en Biomedicina, University of Granada","place":["Granada, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Francisco","family":"Guti\u00e9rrez-Bautista","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology and Immunology III, Faculty of Medicine, University of Granada","place":["Granada, Spain"]},{"name":"Clinical Analysis and Immunology Department, University Hospital Virgen de las Nieves","place":["Granada, Spain"]},{"name":"Institute for Biosanitary Research of Granada (ibs.GRANADA)","place":["Granada, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Garc\u00eda-Aznar","sequence":"additional","affiliation":[{"name":"Health in Code S.L.","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inmaculada","family":"Perea","sequence":"additional","affiliation":[{"name":"Health in Code S.L.","place":["A Coru\u00f1a, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00f3nica","family":"Bernal","sequence":"additional","affiliation":[{"name":"Clinical Analysis and Immunology Department, University Hospital Virgen de las Nieves","place":["Granada, Spain"]},{"name":"Institute for Biosanitary Research of Granada (ibs.GRANADA)","place":["Granada, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel \u00c1ngel","family":"L\u00f3pez-Nevot","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Molecular Biology and Immunology III, Faculty of Medicine, University of Granada","place":["Granada, 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