Amelogenesis Imperfecta as an Emerging Molecular Model for Enamel Biomineralization and Its Implications for Precision Dentistry and Craniofacial Research

Background: Amelogenesis imperfecta (AI) has recently been realized as not only an inherited enamel anomaly, but also a genetically heterogeneous developmental disorder and a compelling model for the study of enamel biomineralization and craniofacial development. Methods: This review is a narrative synthesis of the state of the art of AI genetics, genotype–phenotype relationships, ameloblast biology, enamel biomineralization, molecular diagnosis and new approaches to regeneration by biomimetic nanomaterials, stem cell engineering, use of organoids, 3D bioprinting, and gene editing. Results: Pathogenic variants of enamel matrix proteins, proteolytic enzymes, ion transport, intracellular trafficking, and signaling between cells and the matrix provide insights into different molecular mechanisms underlying hypoplastic, hypomineralized (hypomaturation), and hypomineralized (hypocalcified) disease. The incorporation of new techniques, such as next-generation sequencing, functional genomics, multi-omics, and computational methods is changing the paradigm of AI from phenotype-based classification to one of molecularly stratified and personalized diagnosis. At the same time, emerging experimental approaches—including biomimetic mineralization, engineered ameloblast-like cells, organoid systems, and genome-editing technologies—provide promising platforms for investigating enamel regeneration, although their clinical applicability remains to be established. Conclusions: AI provides a valuable mechanistic framework for advancing research toward patient-specific, biologically informed approaches in developmental biology, precision dentistry, and regenerative craniofacial medicine; however, regenerative interventions remain investigational and require substantial preclinical validation before potential clinical translation.