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Pathogenic variants in\n                    <jats:italic>SF3B4<\/jats:italic>\n                    , which encodes a core spliceosomal component, represent the primary known genetic cause of NS. This review synthesizes recent findings from cellular, zebrafish,\n                    <jats:italic>Xenopus<\/jats:italic>\n                    , and mouse models to elucidate how\n                    <jats:italic>SF3B4<\/jats:italic>\n                    deficiency perturbs neural crest cell (NCC) biology and multi\u2010tissue development. Loss of\n                    <jats:italic>SF3B4<\/jats:italic>\n                    induces widespread splicing abnormalities, with preferential exon skipping affecting AT\u2010rich and GC\u2010poor exons, thereby altering the expression of genes critical for NCC survival, proliferation, migration, and lineage specification. These cellular defects are further exacerbated by oxidative stress and activation of the p53 pathway, resulting in a broad spectrum of developmental abnormalities involving craniofacial, cardiac, skeletal, and sensory (auditory and ocular) systems. Together, these findings highlight the essential role of\n                    <jats:italic>SF3B4<\/jats:italic>\n                    in coordinating early morphogenesis. Cross\u2010species comparisons reveal conserved NCC vulnerabilities alongside model\u2010specific phenotypes, highlighting the challenge of linking individual splicing alterations to distinct structural outcomes in NS. Future research directions include defining tissue\u2010specific\n                    <jats:italic>SF3B4<\/jats:italic>\n                    \u2010dependent splicing targets, developing human induced pluripotent stem cell\u2013derived models, and exploring therapeutic strategies aimed at restoring splicing homeostasis or compensating for disrupted developmental signaling pathways.\n                  <\/jats:p>\n                  <jats:p>\n                    This article is categorized under:\n                    <jats:list list-type=\"simple\">\n                      <jats:list-item>\n                        <jats:p>Congenital Diseases &gt; Molecular and Cellular Physiology<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Congenital Diseases &gt; Genetics\/Genomics\/Epigenetics<\/jats:p>\n                      <\/jats:list-item>\n                      <jats:list-item>\n                        <jats:p>Congenital Diseases &gt; Stem Cells and Development<\/jats:p>\n                      <\/jats:list-item>\n                    <\/jats:list>\n                  <\/jats:p>","DOI":"10.1002\/wsbm.70007","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T02:59:42Z","timestamp":1770778782000},"source":"Crossref","is-referenced-by-count":1,"title":["Nager Syndrome Revisited: Integrating In\u00a0Vivo and In\u00a0Vitro Models to Decipher\n                    <scp>SF3B4<\/scp>\n                    \u2010Dependent Tissue Coordination"],"prefix":"10.1002","volume":"18","author":[{"given":"Jingru","family":"Qin","sequence":"first","affiliation":[{"name":"Laboratory of Developmental Disorders and Toxicology, Center for Promotion of International Education and Research, Faculty of Agriculture Kyushu University  Fukuoka Japan"},{"name":"Graduate School of Bioresource and Bioenvironmental Sciences, Faculty of Agriculture Kyushu University  Fukuoka 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