Nager Syndrome Revisited: Integrating In Vivo and In Vitro Models to Decipher SF3B4-Dependent Tissue Coordination

Nager syndrome (NS) is a rare congenital disorder primarily characterized by mandibulofacial dysostosis and upper limb anomalies. Pathogenic variants in SF3B4, which encodes a core spliceosomal component, represent the primary known genetic cause of NS. This review synthesizes recent findings from cellular, zebrafish, Xenopus, and mouse models to elucidate how SF3B4 deficiency perturbs neural crest cell (NCC) biology and multi-tissue development. Loss of SF3B4 induces widespread splicing abnormalities, with preferential exon skipping affecting AT-rich and GC-poor 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 SF3B4 in coordinating early morphogenesis. Cross-species comparisons reveal conserved NCC vulnerabilities alongside model-specific phenotypes, highlighting the challenge of linking individual splicing alterations to distinct structural outcomes in NS. Future research directions include defining tissue-specific SF3B4-dependent splicing targets, developing human induced pluripotent stem cell-derived models, and exploring therapeutic strategies aimed at restoring splicing homeostasis or compensating for disrupted developmental signaling pathways. This article is categorized under: Congenital Diseases > Molecular and Cellular Physiology Congenital Diseases > Genetics/Genomics/Epigenetics Congenital Diseases > Stem Cells and Development.