RARE DISEASE
Amelogenesis imperfecta
Amelogenesis imperfecta
Amelogenesis imperfecta
Drug discovery
1
drug
With orphan designation
Overview
Amelogenesis imperfecta (AI) is a hereditary enamel development disorder characterized by structural defects in tooth enamel due to genetic mutations affecting proteins critical for amelogenesis. It manifests as hypoplastic (thin enamel), hypocalcified (soft, porous enamel), or hypomaturation (discolored, brittle enamel) forms, with autosomal dominant, recessive, or X-linked inheritance patterns [1][12][17]. Clinical features include tooth sensitivity, discoloration, rapid wear, and increased caries risk. Management focuses on enamel protection, restorative dentistry (e.g., crowns, veneers), and preventive strategies to preserve function and aesthetics [3][8][13].
Burden
High rates of dental caries, enamel fractures, and dentin exposure despite oral hygiene efforts [6][15].
Significant psychosocial impact: aesthetic concerns, social stigma, and reduced quality of life [9][16].
Lifelong treatment needs impose financial costs and procedural complexity, particularly in pediatric and adolescent populations [9][13].
Therapies
Restorative: Composite bonding, stainless steel/pediatric crowns for structural support, and full-coverage prosthetics (e.g., implants) in severe cases [3][6][13].
Preventive: Low-sugar diets, desensitizing agents, and fluoridated products to mitigate sensitivity and decay [8][15].
Multidisciplinary care: Orthodontics for malocclusion and genetic counseling for familial transmission [13][16].
Categories: rare genetic diseases, rare odontological diseases
Research Papers
384 drug discovery papers about Amelogenesis imperfecta, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
384 drug discovery papers about Amelogenesis imperfecta, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-13 | Ufl1-Mediated UFMylation Sustains Amelogenesis by Stabilizing RUNX2.
UFMylation is a conserved ubiquitin-like post-translational modification that controls protein stability and tissue homeostasis, while its role in amelogenesis remains largely uncharacterized. Here, we investigated the function of UFL1, the sole E3 ligase of the UFMylation pathway, in mammalian enamel development using K14-Cre-mediated epithelial-specific Ufl1 knockout mice. Ufl1 ablation caused severe amelogenesis imperfecta, with impaired enamel deposition, hypomineralization, and progressive tooth damage, accompanied by abnormal cervical loop development. Transcriptomic profiling revealed elevated endoplasmic reticulum stress and dysregulated expression of enamel mineralization genes, including significant downregulation of downstream targets of RUNX2, a master regulator of amelogenesis. We further demonstrated that UFL1 and DDRGK1 directly interacted with RUNX2, and UFL1-mediated UFMylation stabilized RUNX2 protein at the post-translational level. Taken together, this study identifies a novel UFMylation-RUNX2 regulatory axis essential for amelogenesis, providing new mechanistic insights into amelogenesis imperfecta and potential therapeutic targets for dental enamel defects.
2026-07-08 | Provisional Shell Crown Technique in the Contemporary Management of Amelogenesis Imperfecta
The tooth preparation and provisionalisation stage in a complex fixed dental reconstruction treatment plan is inherently stressful for both the patient and the clinician. However, when multiple adjacent tooth preparations are deemed clinically indicated, all stakeholders tend to remain satisfied when the outcome of provisional treatment is biomechanically stable and aesthetically pleasing. Digital design and meticulous implementation of the plan can ensure that provisional restoration contours closely match the patient-approved predetermined smile design. Similarly, a careful approach during interim restoration with segmental splinted provisional crowns can lead to a stable restorative outcome, with retention security. This clinical tip article will exemplify the splinted provisional shell crown technique with a focus on the maxillary labial segment dentition.
2026-05-22 | Kdf1 missense mutation caused enamel defects by disrupting cell adhesion and Hippo-YAP signaling in dental epithelium.
Amelogenesis imperfecta is a hereditary enamel defect arising from dental epithelium dysfunction. Although keratinocyte differentiation factor 1 (KDF1) acts as an intracellular regulator in epithelial cells, the underlying disease mechanism of the patient-derived KDF1 missense mutation in amelogenesis remains unclear. Here, we show that a patient-derived KDF1 mutation (c.908 G > C, p.R303P) causes enamel defects by disrupting cell adhesion and Hippo-YAP signaling. Immunohistochemistry revealed strong KDF1 expression throughout dental epithelium development, particularly at the cell membrane. Kdf1 mutation knock-in heterozygotes and homozygotes displayed graded defective enamel with reduced thickness, inadequate mineralization and disorganized microstructure. This phenotype correlated with a gradual reduction in enamel matrix proteins and proteases across genotypes. Bulk RNA sequencing of ameloblasts suggested marked changes in adhesion-related genes and the Hippo-YAP pathway. We characterized cellular consequences of this variant using both LS8 and ALC cell lines, which appeared abnormalities including accelerated proliferation, undermined differentiation, weakened adhesion, and enhanced migration. In vivo and in vitro findings supported a model wherein the KDF1 mutation impaired intercellular and cell-matrix adhesion in ameloblasts. As a result, ameloblast differentiation was hampered through excessive nuclear yes-associated protein (YAP) accumulation and overactivation of downstream proliferative genes. Pharmacological blockade of YAP and TEA domain family member 1 (TEAD1) interaction rescued the mutant phenotypes. Taken together, Kdf1 mutation compromised murine amelogenesis through adhesion defects and subsequent Hippo-YAP dysregulation.
2026-03-19 | Non-Invasive and Holistic Approach to the Functional and Esthetic Rehabilitation of Amelogenesis Imperfecta in Young Patients: A Clinical Study.
Amelogenesis imperfecta (AI) is a hereditary enamel defect that often causes sensitivity, functional limitations, and esthetic concerns in young patients. This clinical study evaluated a non-invasive and holistic approach to rehabilitation using preventive fluoride therapy, pit and fissure sealants, microabrasion, and adhesive composite restorations. Young patients with AI who underwent clinical and radiographic evaluation were the subjects of this clinical study. rehabilitation while maintaining the greatest amount of tooth structure possible. Thin composite veneers were applied using adhesive techniques in a few chosen anterior cases with a higher esthetic demand. Patients showed marked reduction in sensitivity, improved chewing comfort, and enhanced esthetic satisfaction over a six-month follow-up, with high restoration survival and notable psychosocial benefits. The findings suggest that conservative, patient-centered management can effectively restore function and appearance in AI during growth, while preserving tooth structure and supporting overall well-being.
2026-01-05 | Anterior Aesthetic Rehabilitation with Injection Moulding Technique: A Case Series
The injection molding technique has gained popularity for its minimally invasive and time-efficient approach in direct anterior restorations. This case series highlights three clinical cases utilizing injectable resin composite for restoring aesthetics and function in amelogenesis imperfecta and irregularly shaped teeth post-orthodontic treatment. The technique, employing light-cured injectable composite, polymerized through transparent silicone index. The approach ensures optimal composite placement, accurate replication of tooth morphology, minimizes the air entrapment and enhances both the durability and aesthetics of the restoration with a strong marginal seal. The clinical time for the restoration has been considerably reduced thus enhances the patient experience. These cases demonstrate that the injection molding technique is a versatile, provides superior aesthetics, and offers predictable results for anterior direct restorations.
proteins
2026-03-02 | Soluble Notch agonist enables human ameloblast maturation and enamel-like tissue formation for tooth regeneration.
Enamel, the hardest mineralized material in the human body, protects the underlying living tissues, the dentin and pulp of the tooth. However, over 90% of adults have lost or damaged enamel and cannot regenerate the protective structure due to lack of enamel-producing cells, ameloblasts. iPSC-derived secretory Ameloblasts (isAM) have promise in future regenerative dentistry. Today, it is not known why iAM maturation requires intimate contact with the dentin-producing cell type, odontoblast. Here, we reveal that one of the critical signaling ligands emanating from odontoblasts for ameloblast maturation is Delta, the ligand for Notch receptor. We showed that our designed, soluble Notch agonist can induce iAM organoid maturation in an unprecedented manner, without interactions with odontoblast layer. Notably, soluble Notch agonist induces the iAM maturation to a novel, WDR72-positive mature secretory AM stage (ismAM) in our ameloblast organoid model. When transplanted under the kidney capsule of NOD-SCID mice, these ismAM organoids generated enamel-like calcified material, as confirmed by microCT analysis, marking the first demonstration that Notch-activated iAM organoids can form such tissue in vivo. This novel maturation procedure enabled us to analyze the specific requirements of DLX3 function in ameloblasts, independent of its known function in odontoblasts. We now show that DLX3, a gene associated with Amelogenesis Imperfecta, is required on a cell-autonomous manner in human ameloblasts for the expression of Enamelin, MMP20, and WDR72, a role not previously demonstrated in mouse models.
2025-07-18 | Odontogenesis-associated phosphoprotein (ODAPH) Promotes Ameloblast adhesion and alkaline phosphatase (ALP) expression via LAMC2/ ITGB6/TGF-β1 signaling pathway.
Recessive hypomineralized amelogenesis imperfecta has been linked to mutations in Odontogenesis-Associated Phosphoprotein (ODAPH). Consistent with human phenotypes, Odaph-null mice exhibit defective enamel mineralization with ameloblast detachment from the enamel surface. To elucidate the mechanistic basis, we investigated ODAPH's role in ameloblast adhesion and mineralization using ameloblast-lineage cells (ALCs). Key findings demonstrate that Odaph overexpression enhanced Lamininγ2 (LAMC2)/Integrinβ6(ITGB6)/TGF-β1/Alkaline Phosphatase(ALP) pathway activity. Notably, co-immunoprecipitation confirmed interactions between ODAPH and LAMC2. Functional analyses revealed that ITGB6 activates the TGF-β1/ALP signaling cascade. Inhibition of integrin (CWHM-12) abrogates ODAPH-mediated TGF-β1/ALP induction. TGF-β1 positively regulates both LAMC2/ITGB6 expression and ALP activity. These results establish that ODAPH orchestrates ameloblast adhesion and mineralization via the LAMC2/ITGB6/TGF-β1/ALP signaling axis.
2024-10-25 | Deletion within ameloblastin multitargeting domain reduces its interaction with artificial cell membrane.
In human, mutations in the gene encoding the enamel matrix protein ameloblastin (Ambn) have been identified in cases of amelogenesis imperfecta. In mouse models, perturbations in the Ambn gene have caused loss of enamel and dramatic disruptions in enamel-making ameloblast cell function. Critical roles for Ambn in ameloblast cell signaling and polarization as well as adhesion to the nascent enamel matrix have been supported. Recently, we have identified a multitargeting domain (MTD) in Ambn that interacts with cell membrane, with the majority enamel matrix protein amelogenin, and with itself. This domain includes an amphipathic helix (AH) motif that directly interacts with cell membrane. In this study, we analyzed the sequence of the MTD for evolutionary conservation and found high conservation among mammals within the MTD and particularly within the AH motif. We computationally predicted that the AH motif lost its hydrophobic moment upon deleting hydrophobic but not hydrophilic residues from the motif. Furthermore, we rationally designed peptides that encompassed the Ambn MTD and contained deletions of largely hydrophobic or hydrophilic stretches of residues. To assess their AH-forming and membrane-binding abilities, we combined those peptides with synthetic phospholipid membrane vesicles and performed circular dichroism, membrane leakage, and vesicle clearance measurements. Circular dichroism showed retention of α-helix formation in all peptides except the one with the largest deletion of eleven amino acids including seven that were hydrophobic. This same peptide variant failed to cause leakage or clearance of synthetic membranes, while smaller deletions yielded intermediate membrane interaction as measured by leakage and clearance assays. Our data revealed that deletion of key hydrophobic residues from the AH leads to the most dramatic loss of Ambn-membrane interaction. Pinpointing roles of residues within the MTD has important implications for the multifunctionality of Ambn.
2022-10-04 | Enamel defects in Acp4R110C/R110C mice and human ACP4 mutations.
Human ACP4 (OMIM*606362) encodes a transmembrane protein that belongs to histidine acid phosphatase (ACP) family. Recessive mutations in ACP4 cause non-syndromic hypoplastic amelogenesis imperfecta (AI1J, OMIM#617297). While ACP activity has long been detected in developing teeth, its functions during tooth development and the pathogenesis of ACP4-associated AI remain largely unknown. Here, we characterized 2 AI1J families and identified a novel ACP4 disease-causing mutation: c.774_775del, p.Gly260Aspfs*29. To investigate the role of ACP4 during amelogenesis, we generated and characterized Acp4R110C mice that carry the p.(Arg110Cys) loss-of-function mutation. Mouse Acp4 expression was the strongest at secretory stage ameloblasts, and the protein localized primarily at Tomes' processes. While Acp4 heterozygous (Acp4+/R110C) mice showed no phenotypes, incisors and molars of homozygous (Acp4R110C/R110C) mice exhibited a thin layer of aplastic enamel with numerous ectopic mineralized nodules. Acp4R110C/R110C ameloblasts appeared normal initially but underwent pathology at mid-way of secretory stage. Ultrastructurally, sporadic enamel ribbons grew on mineralized dentin but failed to elongate, and aberrant needle-like crystals formed instead. Globs of organic matrix accumulated by the distal membranes of defective Tomes' processes. These results demonstrated a critical role for ACP4 in appositional growth of dental enamel probably by processing and regulating enamel matrix proteins around mineralization front apparatus.
2021-10-20 | Molecular Cloning of Mouse Homologue of Enamel Protein C4orf26 and Its Phosphorylation by FAM20C.
It is widely accepted that cellular processes are controlled by protein phosphorylation and has become increasingly clear that protein degradation, localization and conformation as well as protein-protein interaction are the examples of subsequent cellular events modulated by protein phosphorylation. Enamel matrix proteins belong to members of the secretory calcium binding phosphoprotein (SCPP) family clustered on chromosome 4q21, and most of the SCPP phosphoproteins have at least one S-X-E motifs (S; serine, X; any amino acid, E; glutamic acid). It has been reported that mutations in C4orf26 gene, located on chromosome 4q21, are associated with autosomal recessive type of Amelogenesis Imperfecta (AI), a hereditary condition that affects enamel formation/mineralization. The enamel phenotype observed in patients with C4orf26 mutations is hypomineralized and partially hypoplastic, indicating that C4orf26 protein may function at both secretory and maturation stages of amelogenesis. The previous in vitro study showed that the synthetic phosphorylated peptide based on C4orf26 protein sequence accelerates hydroxyapatite nucleation. Here we show the molecular cloning of Gm1045, mouse homologue of C4orf26, which has 2 splicing isoforms. Immunohistochemical analysis demonstrated that the immunolocalization of Gm1045 is mainly observed in enamel matrix in vivo. Our report is the first to show that FAM20C, the Golgi casein kinase, phosphorylates C4orf26 and Gm1045 in cell cultures. The extracellular localization of C4orf26/Gm1045 was regulated by FAM20C kinase activity. Thus, our data point out the biological importance of enamel matrix-kinase control of SCPP phosphoproteins and may have a broad impact on the regulation of amelogenesis and AI.
gene therapies
2026-08-06 | Fam83h affected adhesion ability and extracellular matrix collagen formation in ameloblasts.
Amelogenesis imperfecta (AI) is a group of inherited diseases characterized by enamel defects. Mutation in multiple genes may cause AI. The objective of this study was to investigate the specific roles of Family with sequence similarity 83 member H (FAM83H) in AI and determine its effect on ameloblasts. To investigate the impact of Fam83h on ameloblast gene expression, we utilized ameloblast line HAT-7 cells with knockdown of Fam83h gene for transcriptome sequencing. The experimental cell samples were undergone library preparation and RNA sequencing expreiments. Cell Adhesion test kit was employed to evaluate the influence of Fam83h on HAT-7 cell adhesion ability. RT-qPCR and western blot were conducted to analyze the expression levels of integrin and collagen proteins upon downregulation of Fam83h. RNA-seq analysis revealed differential expression of 572 genes in HAT-7 cells with knockdown of Fam83h gene, including 285 up-regulated genes and 287 down-regulated genes. GO and KEGG enrichment analysis indicated that Fam83h could modulate collagen synthesis in ameloblasts as well as affect the focal adhesion pathway. In the cell adhesion assay, we observed a decrease in adhesion ability due to downregulation of Fam83h in HAT-7 cell line. Furthermore, it was found that Fam83h can upregulated extracellular matrix collagen formation in ameloblasts. Fam83h may affect the adhesion ability and extracellular matrix collagen formation in ameloblasts, leading to AI.
2026-08-06 | Fam83h affected adhesion ability and extracellular matrix collagen formation in ameloblasts
Amelogenesis imperfecta (AI) is a group of inherited diseases characterized by enamel defects. Mutation in multiple genes may cause AI. The objective of this study was to investigate the specific roles of Family with sequence similarity 83 member H (FAM83H) in AI and determine its effect on ameloblasts. To investigate the impact of Fam83h on ameloblast gene expression, we utilized ameloblast line HAT-7 cells with knockdown of Fam83h gene for transcriptome sequencing. The experimental cell samples were undergone library preparation and RNA sequencing expreiments. Cell Adhesion test kit was employed to evaluate the influence of Fam83h on HAT-7 cell adhesion ability. RT-qPCR and western blot were conducted to analyze the expression levels of integrin and collagen proteins upon downregulation of Fam83h. RNA-seq analysis revealed differential expression of 572 genes in HAT-7 cells with knockdown of Fam83h gene, including 285 up-regulated genes and 287 down-regulated genes. GO and KEGG enrichment analysis indicated that Fam83h could modulate collagen synthesis in ameloblasts as well as affect the focal adhesion pathway. In the cell adhesion assay, we observed a decrease in adhesion ability due to downregulation of Fam83h in HAT-7 cell line. Furthermore, it was found that Fam83h can upregulated extracellular matrix collagen formation in ameloblasts. Fam83h may affect the adhesion ability and extracellular matrix collagen formation in ameloblasts, leading to AI.
2026-04-24 | Slc13a5 Expression in Ameloblast-Like Cells and Tooth Organ Cultures: A Platform for Therapeutic Studies
Mutations in SLC13A5, encoding the sodium-dependent citrate transporter (NaCT), cause developmental and epileptic encephalopathy 25 (DEE25), a disorder characterized by severe neurological impairment and enamel defects, including hypoplastic amelogenesis imperfecta. Although the neurological features of DEE25 are well documented, the mechanisms underlying enamel abnormalities remain poorly understood. In this study, we established in vitro and ex vivo systems to investigate NaCT function in enamel development and to support future gene therapy approaches. Mouse ameloblast-like LS8 cells were transfected with Slc13a5 expression plasmids to evaluate transfection efficiency, as well as gene and protein expression. Transient overexpression of Slc13a5 resulted in increased mRNA levels and detectable NaCT protein, with peak transcript expression at 48 hours and maximal protein and GFP reporter signal at 72 hours post- transfection. Immunocytochemistry further confirmed successful NaCT expression. To model enamel defects ex vivo, tooth organ cultures were established from wild-type and Slc13a5 R337*/R337* mouse molars. Mutant tooth germs in culture reproduced key pathological features observed in vivo, including irregular, ectopic mineral deposition. These findings demonstrate that the organ culture system can partially recapitulate the in vivo phenotype and serve as a platform for evaluating short-term gene delivery efficiency. Together, these results validate LS8 cells and tooth organ cultures as complementary platforms for studying Slc13a5 function and optimizing gene delivery strategies. This work provides a foundational step toward the development of adeno-associated virus (AAV)-based therapeutic approaches aimed at mitigating NaCT function and improving enamel defects associated with DEE25.
2026-03-07 | Generation and characterization of a murine amelogenesis imperfecta model.
Amelogenesis imperfecta (AI) refers to a group of rare yet complex genetic disorders that affect the quantity and/or quality of tooth enamel. Recently, in AI patients, we identified mutations that disrupt a conserved alternative splicing pattern of the AMELX gene, which encodes amelogenin, the most abundant enamel matrix protein. These mutations led to the retention of exon 4, which is normally skipped during the pre-mRNA splicing process, resulting in the characteristic pitted, hypoplastic, and hypomineralized enamel defects. To observe the impact of retention of exon 4 within AMELX, a gene edited knock-in mouse model was generated. A single-nucleotide knock-in mouse model was generated using CRISPR/Cas9 technology to introduce a silent mutation (NM_001415990.1: c.120 T>C, p.(Ala40=)) that abrogated alternative splicing of exon 4. Following genomic sequence validation, the successfully-targeted mice were propagated, and their offspring genotyped for characterization. Micro-computed tomography analysis and immunohistochemistry analysis were performed on the hemi-mandibles of the wild-type and the knock-in mice. The enamel of the knock-in mice was chalky white and lacked translucency, due to faulty mineralization. This defective enamel broke down soon after tooth eruption. During the maturation stage, the ameloblast layer lost its cellular polarity and homogeneity, and intermingled with adjacent cell types to form disorganized clusters. The validated and characterized Amelx c.120 T>C mouse model provides a useful platform for investigating the molecular pathophysiology associated with retention of the exon 4 sequence. Following systemic characterization, this mouse model will serve as an important tool for assessing therapeutic strategies aimed at ameliorating the disease phenotype.
2025-12-30 | Epidermolysis bullosa accompanied by amelogenesis imperfecta: A report of three cases and literature review
Introduction: Epidermolysis Bullosa (EB) is a group of genetic disorders characterized by skin and mucosal fragility. Similarly, Amelogenesis Imperfecta (AI) is a genetic condition that affects the development of dental enamel, leading to structural anomalies. Specific gene mutations, such as those affecting COL17A1, are known to cause both conditions, notably in patients with Junctional EB. This study explores the clinical presentations of three patients diagnosed with both AI and EB, with two cases confirmed to have COL17A1 mutations, linking the genetic mutation to both enamel defects and EBs. Case Reports: The clinical findings from three patients are reported. Two of the cases were diagnosed with Junctional EB, with genetic testing confirming COL17A1 mutations, which correlated with the presentation of hypoplastic enamel and pitting. All patients exhibited gingivitis and oral mucosal fragility, which posed challenges in maintaining oral hygiene. Discussion: Maintaining oral hygiene in patients with EB is particularly challenging due to the fragility of their oral mucosa. These challenges are exacerbated by the low socioeconomic status of the patients, limiting access to proper oral care tools. The study explores oral management strategies, including the use of soft toothbrushes, sucralfate for ulcer management, and the importance of a multidisciplinary approach. Regular dental check-ups and early intervention are emphasized as essential for improving patient outcomes and quality of life. Conclusion: It is crucial for dental practitioners to identify signs of AI in EB patients and to ensure timely referrals and consultations. Furthermore, EB patients should be referred to dental professionals early to prevent oral complications. A multidisciplinary approach is vital for addressing the complex needs of these patients effectively.
cell therapies
2024-06-25 | Protocol for generating three-dimensional induced early ameloblasts using serum-free media and growth factors.
Adult humans cannot regenerate the enamel-forming cell type, ameloblasts. Hence, human induced pluripotent stem cell (hiPSC)-derived ameloblasts are valuable for investigating tooth development and regeneration. Here, we present a protocol for generating three-dimensional induced early ameloblasts (ieAMs) utilizing serum-free media and growth factors. We describe steps for directing hiPSCs toward oral epithelium and then toward ameloblast fate. These cells can form suspended early ameloblast organoids. This approach is critical for understanding, treating, and promoting regeneration in diseases like amelogenesis imperfecta. For complete details on the use and execution of this protocol, please refer to Alghadeer et al.1.
2024-06-16 | Regenerative Endodontic Procedures in Immature Teeth Affected by Regional Odontodysplasia.
Regional odontodysplasia (ROD) is a rare developmental disorder characterized by hypo-mineralization and hypoplasia of enamel and dentin. Symptoms include poorly developed tooth buds, delayed eruption of permanent teeth in affected quadrants, and ghost teeth. The affected teeth often become necrotic due to abnormal enamel and dentin development, making them susceptible to caries and infection. The aim of this case report is to describe the treatment of ROD through pulp revascularization. A 13-year-old girl was referred for endodontic treatment. The mandibular left incisors and first premolar, which were affected by regional odontodysplasia, lost their vitality because of the impaired structure of the enamel. Due to the teeth's early developmental stage, a regenerative endodontic treatment was attempted. All 3 teeth were treated using the same protocol following the AAE guidelines. After 4 weeks, treatment of the premolar was completed, whereas the incisor teeth remained symptomatic and were and therefore, intracanal dressing with calcium hydroxide was repeated and left in place for 5 months. Finally, the regenerative procedure was completed, and the crowns were restored. The patient was scheduled for follow-up examinations after 6 months, and then yearly for the next 3 years. After 1 year, the periapical lesion around the central incisor and premolar had resolved, the lesion around the apex of the lateral incisor was healing, and the roots had continued to develop. After 3 years, complete healing and pulp canal obliteration were observed in the central incisor and in the premolar. However, the root of the lateral incisor tooth was split, and it was recommended to extract this tooth. The positive outcomes of regenerative endodontics in the central incisor and premolar suggest that revascularization of the pulp may be optional for the treatment of immature necrotic teeth affected by developmental disorders, such as ROD, amelogenesis imperfecta, or dentinogenesis imperfecta.
2024-03-18 | From Pluripotent Stem Cells to Organoids and Bioprinting: Recent Advances in Dental Epithelium and Ameloblast Models to Study Tooth Biology and Regeneration
Abstract Ameloblasts are the specialized dental epithelial cell type responsible for enamel formation. Following completion of enamel development in humans, ameloblasts are lost and biological repair or regeneration of enamel is not possible. In the past, in vitro models to study dental epithelium and ameloblast biology were limited to freshly isolated primary cells or immortalized cell lines, both with limited translational potential. In recent years, large strides have been made with the development of induced pluripotent stem cell and organoid models of this essential dental lineage – both enabling modeling of human dental epithelium. Upon induction with several different signaling factors (such as transforming growth factor and bone morphogenetic proteins) these models display elevated expression of ameloblast markers and enamel matrix proteins. The advent of 3D bioprinting, and its potential combination with these advanced cellular tools, is poised to revolutionize the field – and its potential for tissue engineering, regenerative and personalized medicine. As the advancements in these technologies are rapidly evolving, we evaluate the current state-of-the-art regarding in vitro cell culture models of dental epithelium and ameloblast lineage with a particular focus toward their applicability for translational tissue engineering and regenerative/personalized medicine. Graphical Abstract Future perspectives for in vitro modeling of dental epithelium and ameloblasts. Development of iPSC and organoid models that can reliably generate dental epithelium and ameloblast-like cells, together with advances in 3D bioprinting, provide promising tools for enamel research. Advanced models will provide new avenues for development of enamel repair/regeneration approaches, for testing of dental materials or drugs, studying host-pathogen and/or cell-cell interactions, in vitro modeling of enamel diseases (e.g. amelogenesis imperfecta) and developing novel insights in fundamental tooth biology (e.g. regulation of amelogenesis, lineage specification). Abbreviations: iPSC: induced pluripotent stem cells; TO: tooth organoids; DE: dental epithelium; AB: ameloblast.
2023-11-07 | Single-cell census of human tooth development enables generation of human enamel.
Tooth enamel secreted by ameloblasts (AMs) is the hardest material in the human body, acting as a shield to protect the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here, we use single-cell combinatorial indexing RNA sequencing (sci-RNA-seq) to establish a spatiotemporal single-cell census for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We identify key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in human ameloblast in vitro differentiation from induced pluripotent stem cells (iPSCs). We furthermore develop a disease model of amelogenesis imperfecta in a three-dimensional (3D) organoid system and show AM maturation to mineralized structure in vivo. These studies pave the way for future regenerative dentistry.
2021-07-03 | Stage-Specific Role of Amelx Activation in Stepwise Ameloblast Induction from Mouse Induced Pluripotent Stem Cells
Amelogenin comprises ~90% of enamel proteins; however, the involvement of Amelx transcriptional activation in regulating ameloblast differentiation from induced pluripotent stem cells (iPSCs) remains unknown. In this study, we generated doxycycline-inducible Amelx-expressing mouse iPSCs (Amelx-iPSCs). We then established a three-stage ameloblast induction strategy from Amelx-iPSCs, including induction of surface ectoderm (stage 1), dental epithelial cells (DECs; stage 2), and ameloblast lineage (stage 3) in sequence, by manipulating several signaling molecules. We found that adjunctive use of lithium chloride (LiCl) in addition to bone morphogenetic protein 4 and retinoic acid promoted concentration-dependent differentiation of DECs. The resulting cells had a cobblestone appearance and keratin14 positivity. Attenuation of LiCl at stage 3 together with transforming growth factor β1 and epidermal growth factor resulted in an ameloblast lineage with elongated cell morphology, positivity for ameloblast markers, and calcium deposition. Although stage-specific activation of Amelx did not produce noticeable phenotypic changes in ameloblast differentiation, Amelx activation at stage 3 significantly enhanced cell adhesion as well as decreased proliferation and migration. These results suggest that the combination of inducible Amelx transcription and stage-specific ameloblast induction for iPSCs represents a powerful tool to highlight underlying mechanisms in ameloblast differentiation and function in association with Amelx expression.
other
2023-03-07 | Amelogenesis imperfecta in a Chinese family resulting from a FAM83H variation and the effect of FAM83H on the secretion of enamel matrix proteins.
To investigate the variant of an amelogenesis imperfecta (AI) family and to explore the function of the FAM83H (family with sequence similarity 83 member H) in the enamel formation. We investigated a five-generation Chinese family diagnosed with AI; clinical data was collected, whole-exome sequencing (WES) was conducted to explore the pathogenic gene and variants and Sanger sequencing was used to verify the variants. The three-dimensional protein structures of wild-type and mutant FAM83H were predicted using alpha fold 2. To study the possible regulatory function of Fam83h on amelogenesis, immunolocalization was performed to observe the expression of Fam83h protein in Sprague-Dawley rat postnatal incisors. The mRNA and protein level of amelogenin, enamelin, kallikrein-related peptidase-4 and ameloblastin were also detected after the Fam83h was knocked down by small interfering RNA (siRNA) in HAT-7 cells. A known nonsense variant (c.973 C > T) in exon 5 of FAM83H gene was found in this family, causing a truncated protein (p.R325X). Immunolocalization of Fam83h in Sprague-Dawley rat postnatal incisors showed that Fam83h protein expression was detected in presecretory and secretory stages. When Fam83h expression was reduced by siRNA, the expression of amelogenin, enamelin, kallikrein-related peptidase-4 decreased. However, the expression of ameloblastin increased. FAM83H gene variant (c.973 C > T) causes AI. FAM83H regulates the secretion of enamel matrix proteins and affects ameloblast differentiation. This study provided that FAM83H variants could influence enamel formation and provided new insights into the pathogenesis of AI.
2022-11-17 | N6-methyladenosine (m6A) RNA methylation mediated by methyltransferase complex subunit WTAP regulates amelogenesis
N6-methyladenosine (m6A) RNA methylation, one of the most widespread posttranscriptional modifications in eukaryotes, plays crucial roles in various developmental processes. The m6A modification process is catalyzed by a methyltransferase complex that includes Wilms tumor 1-associated protein (WTAP) as a key component. Whether the development of dental enamel is regulated by m6A RNA methylation in mammals remains unclear. Here, we reveal that WTAP is widely expressed from the early stage of tooth development. Specific inactivation of Wtap in mouse enamel epithelium by the Cre/loxp system leads to serious developmental defects in amelogenesis. In Wtap conditional KO mice, we determined that the differentiation of enamel epithelial cells into mature ameloblasts at the early stages of enamel development is affected. Mechanistically, loss of Wtap inhibits the expression of Sonic hedgehog (SHH), which plays an important role in the generation of ameloblasts from stem cells. Together, our findings provide new insights into the functional role of WTAP-mediated m6A methylation in amelogenesis in mammals.
2022-07-26 | MiR-148a-3p Regulates Stem Cell Osteogenic Differentiation and Enamel Development by Targeting Runt-Related Transcription Factor 2 and E-cadherin <i>via</i> the Wnt1/β-catenin Signaling Pathway
We aimed to evaluate the regulatory effects of miR-148a-3p on stem cell osteogenic differentiation and enamel development by targeting runt-related transcription factor 2 (RUNX2) and E-cadherin, respectively. TargetScan software was utilized to predict the binding sites between miR-148a-3p and osteogenic marker gene RUNX2 or E-cadherin. The changes in miR-148a-3p expression during osteogenic differentiation of epidermal stem cells were detected. After transfection with miR-148a-3p mimics or miR-148a-3p inhibitor, epidermal stem cells were induced towards osteogenic differentiation, and the changes in RUNX2 expression were measured. The changes in miR-148a-3p expression during enamel development regulated by epidermal stem cells were determined. After liposome-mediated transfection with miR-148a-3p mimics or miR-148a-3p inhibitor, epidermal stem cells were induced towards ameloblast development. Cell proliferation and apoptosis abilities were tested using methyl thiazolyl tetrazolium assay and flow cytometry, respectively. The expression of miR-148a-3p was detected by RT-PCR. The protein expressions of Wnt1, β-catenin, RUNX2 and E-cadherin were measured by Western blotting. Epidermal stem cells differentiated into osteoblasts through osteogenic induction culture. On 5, 12, 15 and 30 d, epidermal stem cells gradually differentiated into osteoblasts through epithelial aggregation and depression, mesenchymal aggregation, and dentin and enamel secretion. After transfection, compared with negative control (NC) group, the cell viability of miR-148-3p group significantly decreased (P<0.05), and the apoptosis rate increased (P<0.01). The viability of miR-148-3p inhibitor group significantly increased (P<0.05), while the apoptosis rate reduced (P<0.01). The dual-luciferase reporter assay showed that miR-148a-3p targeted Wnt1. Compared with NC group, the expression of miR-148a-3p significantly rose in miR-148a-3p group (P<0.001), and the protein expression levels of Wnt1, β-catenin, RUNX2 and E-cadherin significantly decreased. Compared with NC group, the expression of miR-148a-3p in miR-148a-3p inhibitor group significantly decreased (P<0.05), and the protein expression levels of Wnt1, β-catenin, RUNX2 and E-cadherin significantly increased. MiR-148a-3p is highly expressed in and regulates osteogenic differentiation and enamel development through targeting RUNX2 and E-cadherin respectively via the Wnt1/β-catenin pathway, which plays an important role in cell differentiation, stem cell proliferation and enamel development.
2021-06-01 | Overexpression of miR-1306-5p, miR-3195, and miR-3914 Inhibits Ameloblast Differentiation through Suppression of Genes Associated with Human Amelogenesis Imperfecta.
Amelogenesis imperfecta is a congenital form of enamel hypoplasia. Although a number of genetic mutations have been reported in humans, the regulatory network of these genes remains mostly unclear. To identify signatures of biological pathways in amelogenesis imperfecta, we conducted bioinformatic analyses on genes associated with the condition in humans. Through an extensive search of the main biomedical databases, we found 56 genes in which mutations and/or association/linkage were reported in individuals with amelogenesis imperfecta. These candidate genes were further grouped by function, pathway, protein-protein interaction, and tissue-specific expression patterns using various bioinformatic tools. The bioinformatic analyses highlighted a group of genes essential for extracellular matrix formation. Furthermore, advanced bioinformatic analyses for microRNAs (miRNAs), which are short non-coding RNAs that suppress target genes at the post-transcriptional level, predicted 37 candidates that may be involved in amelogenesis imperfecta. To validate the miRNA-gene regulation association, we analyzed the target gene expression of the top seven candidate miRNAs: miR-3195, miR-382-5p, miR-1306-5p, miR-4683, miR-6716-3p, miR-3914, and miR-3935. Among them, miR-1306-5p, miR-3195, and miR-3914 were confirmed to regulate ameloblast differentiation through the regulation of genes associated with amelogenesis imperfecta in AM-1 cells, a human ameloblastoma cell line. Taken together, our study suggests a potential role for miRNAs in amelogenesis imperfecta.
2017-03-13 | MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways–Novel Insight into the Origins of Enamel Pathologies
Abstract Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3′-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI.
small molecules
2026-07-13 | Ufl1-Mediated UFMylation Sustains Amelogenesis by Stabilizing RUNX2.
UFMylation is a conserved ubiquitin-like post-translational modification that controls protein stability and tissue homeostasis, while its role in amelogenesis remains largely uncharacterized. Here, we investigated the function of UFL1, the sole E3 ligase of the UFMylation pathway, in mammalian enamel development using K14-Cre-mediated epithelial-specific Ufl1 knockout mice. Ufl1 ablation caused severe amelogenesis imperfecta, with impaired enamel deposition, hypomineralization, and progressive tooth damage, accompanied by abnormal cervical loop development. Transcriptomic profiling revealed elevated endoplasmic reticulum stress and dysregulated expression of enamel mineralization genes, including significant downregulation of downstream targets of RUNX2, a master regulator of amelogenesis. We further demonstrated that UFL1 and DDRGK1 directly interacted with RUNX2, and UFL1-mediated UFMylation stabilized RUNX2 protein at the post-translational level. Taken together, this study identifies a novel UFMylation-RUNX2 regulatory axis essential for amelogenesis, providing new mechanistic insights into amelogenesis imperfecta and potential therapeutic targets for dental enamel defects.
2026-07-08 | Provisional Shell Crown Technique in the Contemporary Management of Amelogenesis Imperfecta
The tooth preparation and provisionalisation stage in a complex fixed dental reconstruction treatment plan is inherently stressful for both the patient and the clinician. However, when multiple adjacent tooth preparations are deemed clinically indicated, all stakeholders tend to remain satisfied when the outcome of provisional treatment is biomechanically stable and aesthetically pleasing. Digital design and meticulous implementation of the plan can ensure that provisional restoration contours closely match the patient-approved predetermined smile design. Similarly, a careful approach during interim restoration with segmental splinted provisional crowns can lead to a stable restorative outcome, with retention security. This clinical tip article will exemplify the splinted provisional shell crown technique with a focus on the maxillary labial segment dentition.
2026-05-22 | Kdf1 missense mutation caused enamel defects by disrupting cell adhesion and Hippo-YAP signaling in dental epithelium.
Amelogenesis imperfecta is a hereditary enamel defect arising from dental epithelium dysfunction. Although keratinocyte differentiation factor 1 (KDF1) acts as an intracellular regulator in epithelial cells, the underlying disease mechanism of the patient-derived KDF1 missense mutation in amelogenesis remains unclear. Here, we show that a patient-derived KDF1 mutation (c.908 G > C, p.R303P) causes enamel defects by disrupting cell adhesion and Hippo-YAP signaling. Immunohistochemistry revealed strong KDF1 expression throughout dental epithelium development, particularly at the cell membrane. Kdf1 mutation knock-in heterozygotes and homozygotes displayed graded defective enamel with reduced thickness, inadequate mineralization and disorganized microstructure. This phenotype correlated with a gradual reduction in enamel matrix proteins and proteases across genotypes. Bulk RNA sequencing of ameloblasts suggested marked changes in adhesion-related genes and the Hippo-YAP pathway. We characterized cellular consequences of this variant using both LS8 and ALC cell lines, which appeared abnormalities including accelerated proliferation, undermined differentiation, weakened adhesion, and enhanced migration. In vivo and in vitro findings supported a model wherein the KDF1 mutation impaired intercellular and cell-matrix adhesion in ameloblasts. As a result, ameloblast differentiation was hampered through excessive nuclear yes-associated protein (YAP) accumulation and overactivation of downstream proliferative genes. Pharmacological blockade of YAP and TEA domain family member 1 (TEAD1) interaction rescued the mutant phenotypes. Taken together, Kdf1 mutation compromised murine amelogenesis through adhesion defects and subsequent Hippo-YAP dysregulation.
2026-03-19 | Non-Invasive and Holistic Approach to the Functional and Esthetic Rehabilitation of Amelogenesis Imperfecta in Young Patients: A Clinical Study.
Amelogenesis imperfecta (AI) is a hereditary enamel defect that often causes sensitivity, functional limitations, and esthetic concerns in young patients. This clinical study evaluated a non-invasive and holistic approach to rehabilitation using preventive fluoride therapy, pit and fissure sealants, microabrasion, and adhesive composite restorations. Young patients with AI who underwent clinical and radiographic evaluation were the subjects of this clinical study. rehabilitation while maintaining the greatest amount of tooth structure possible. Thin composite veneers were applied using adhesive techniques in a few chosen anterior cases with a higher esthetic demand. Patients showed marked reduction in sensitivity, improved chewing comfort, and enhanced esthetic satisfaction over a six-month follow-up, with high restoration survival and notable psychosocial benefits. The findings suggest that conservative, patient-centered management can effectively restore function and appearance in AI during growth, while preserving tooth structure and supporting overall well-being.
2026-01-05 | Anterior Aesthetic Rehabilitation with Injection Moulding Technique: A Case Series
The injection molding technique has gained popularity for its minimally invasive and time-efficient approach in direct anterior restorations. This case series highlights three clinical cases utilizing injectable resin composite for restoring aesthetics and function in amelogenesis imperfecta and irregularly shaped teeth post-orthodontic treatment. The technique, employing light-cured injectable composite, polymerized through transparent silicone index. The approach ensures optimal composite placement, accurate replication of tooth morphology, minimizes the air entrapment and enhances both the durability and aesthetics of the restoration with a strong marginal seal. The clinical time for the restoration has been considerably reduced thus enhances the patient experience. These cases demonstrate that the injection molding technique is a versatile, provides superior aesthetics, and offers predictable results for anterior direct restorations.
proteins
2026-03-02 | Soluble Notch agonist enables human ameloblast maturation and enamel-like tissue formation for tooth regeneration.
Enamel, the hardest mineralized material in the human body, protects the underlying living tissues, the dentin and pulp of the tooth. However, over 90% of adults have lost or damaged enamel and cannot regenerate the protective structure due to lack of enamel-producing cells, ameloblasts. iPSC-derived secretory Ameloblasts (isAM) have promise in future regenerative dentistry. Today, it is not known why iAM maturation requires intimate contact with the dentin-producing cell type, odontoblast. Here, we reveal that one of the critical signaling ligands emanating from odontoblasts for ameloblast maturation is Delta, the ligand for Notch receptor. We showed that our designed, soluble Notch agonist can induce iAM organoid maturation in an unprecedented manner, without interactions with odontoblast layer. Notably, soluble Notch agonist induces the iAM maturation to a novel, WDR72-positive mature secretory AM stage (ismAM) in our ameloblast organoid model. When transplanted under the kidney capsule of NOD-SCID mice, these ismAM organoids generated enamel-like calcified material, as confirmed by microCT analysis, marking the first demonstration that Notch-activated iAM organoids can form such tissue in vivo. This novel maturation procedure enabled us to analyze the specific requirements of DLX3 function in ameloblasts, independent of its known function in odontoblasts. We now show that DLX3, a gene associated with Amelogenesis Imperfecta, is required on a cell-autonomous manner in human ameloblasts for the expression of Enamelin, MMP20, and WDR72, a role not previously demonstrated in mouse models.
2025-07-18 | Odontogenesis-associated phosphoprotein (ODAPH) Promotes Ameloblast adhesion and alkaline phosphatase (ALP) expression via LAMC2/ ITGB6/TGF-β1 signaling pathway.
Recessive hypomineralized amelogenesis imperfecta has been linked to mutations in Odontogenesis-Associated Phosphoprotein (ODAPH). Consistent with human phenotypes, Odaph-null mice exhibit defective enamel mineralization with ameloblast detachment from the enamel surface. To elucidate the mechanistic basis, we investigated ODAPH's role in ameloblast adhesion and mineralization using ameloblast-lineage cells (ALCs). Key findings demonstrate that Odaph overexpression enhanced Lamininγ2 (LAMC2)/Integrinβ6(ITGB6)/TGF-β1/Alkaline Phosphatase(ALP) pathway activity. Notably, co-immunoprecipitation confirmed interactions between ODAPH and LAMC2. Functional analyses revealed that ITGB6 activates the TGF-β1/ALP signaling cascade. Inhibition of integrin (CWHM-12) abrogates ODAPH-mediated TGF-β1/ALP induction. TGF-β1 positively regulates both LAMC2/ITGB6 expression and ALP activity. These results establish that ODAPH orchestrates ameloblast adhesion and mineralization via the LAMC2/ITGB6/TGF-β1/ALP signaling axis.
2024-10-25 | Deletion within ameloblastin multitargeting domain reduces its interaction with artificial cell membrane.
In human, mutations in the gene encoding the enamel matrix protein ameloblastin (Ambn) have been identified in cases of amelogenesis imperfecta. In mouse models, perturbations in the Ambn gene have caused loss of enamel and dramatic disruptions in enamel-making ameloblast cell function. Critical roles for Ambn in ameloblast cell signaling and polarization as well as adhesion to the nascent enamel matrix have been supported. Recently, we have identified a multitargeting domain (MTD) in Ambn that interacts with cell membrane, with the majority enamel matrix protein amelogenin, and with itself. This domain includes an amphipathic helix (AH) motif that directly interacts with cell membrane. In this study, we analyzed the sequence of the MTD for evolutionary conservation and found high conservation among mammals within the MTD and particularly within the AH motif. We computationally predicted that the AH motif lost its hydrophobic moment upon deleting hydrophobic but not hydrophilic residues from the motif. Furthermore, we rationally designed peptides that encompassed the Ambn MTD and contained deletions of largely hydrophobic or hydrophilic stretches of residues. To assess their AH-forming and membrane-binding abilities, we combined those peptides with synthetic phospholipid membrane vesicles and performed circular dichroism, membrane leakage, and vesicle clearance measurements. Circular dichroism showed retention of α-helix formation in all peptides except the one with the largest deletion of eleven amino acids including seven that were hydrophobic. This same peptide variant failed to cause leakage or clearance of synthetic membranes, while smaller deletions yielded intermediate membrane interaction as measured by leakage and clearance assays. Our data revealed that deletion of key hydrophobic residues from the AH leads to the most dramatic loss of Ambn-membrane interaction. Pinpointing roles of residues within the MTD has important implications for the multifunctionality of Ambn.
2022-10-04 | Enamel defects in Acp4R110C/R110C mice and human ACP4 mutations.
Human ACP4 (OMIM*606362) encodes a transmembrane protein that belongs to histidine acid phosphatase (ACP) family. Recessive mutations in ACP4 cause non-syndromic hypoplastic amelogenesis imperfecta (AI1J, OMIM#617297). While ACP activity has long been detected in developing teeth, its functions during tooth development and the pathogenesis of ACP4-associated AI remain largely unknown. Here, we characterized 2 AI1J families and identified a novel ACP4 disease-causing mutation: c.774_775del, p.Gly260Aspfs*29. To investigate the role of ACP4 during amelogenesis, we generated and characterized Acp4R110C mice that carry the p.(Arg110Cys) loss-of-function mutation. Mouse Acp4 expression was the strongest at secretory stage ameloblasts, and the protein localized primarily at Tomes' processes. While Acp4 heterozygous (Acp4+/R110C) mice showed no phenotypes, incisors and molars of homozygous (Acp4R110C/R110C) mice exhibited a thin layer of aplastic enamel with numerous ectopic mineralized nodules. Acp4R110C/R110C ameloblasts appeared normal initially but underwent pathology at mid-way of secretory stage. Ultrastructurally, sporadic enamel ribbons grew on mineralized dentin but failed to elongate, and aberrant needle-like crystals formed instead. Globs of organic matrix accumulated by the distal membranes of defective Tomes' processes. These results demonstrated a critical role for ACP4 in appositional growth of dental enamel probably by processing and regulating enamel matrix proteins around mineralization front apparatus.
2021-10-20 | Molecular Cloning of Mouse Homologue of Enamel Protein C4orf26 and Its Phosphorylation by FAM20C.
It is widely accepted that cellular processes are controlled by protein phosphorylation and has become increasingly clear that protein degradation, localization and conformation as well as protein-protein interaction are the examples of subsequent cellular events modulated by protein phosphorylation. Enamel matrix proteins belong to members of the secretory calcium binding phosphoprotein (SCPP) family clustered on chromosome 4q21, and most of the SCPP phosphoproteins have at least one S-X-E motifs (S; serine, X; any amino acid, E; glutamic acid). It has been reported that mutations in C4orf26 gene, located on chromosome 4q21, are associated with autosomal recessive type of Amelogenesis Imperfecta (AI), a hereditary condition that affects enamel formation/mineralization. The enamel phenotype observed in patients with C4orf26 mutations is hypomineralized and partially hypoplastic, indicating that C4orf26 protein may function at both secretory and maturation stages of amelogenesis. The previous in vitro study showed that the synthetic phosphorylated peptide based on C4orf26 protein sequence accelerates hydroxyapatite nucleation. Here we show the molecular cloning of Gm1045, mouse homologue of C4orf26, which has 2 splicing isoforms. Immunohistochemical analysis demonstrated that the immunolocalization of Gm1045 is mainly observed in enamel matrix in vivo. Our report is the first to show that FAM20C, the Golgi casein kinase, phosphorylates C4orf26 and Gm1045 in cell cultures. The extracellular localization of C4orf26/Gm1045 was regulated by FAM20C kinase activity. Thus, our data point out the biological importance of enamel matrix-kinase control of SCPP phosphoproteins and may have a broad impact on the regulation of amelogenesis and AI.
gene therapies
2026-08-06 | Fam83h affected adhesion ability and extracellular matrix collagen formation in ameloblasts.
Amelogenesis imperfecta (AI) is a group of inherited diseases characterized by enamel defects. Mutation in multiple genes may cause AI. The objective of this study was to investigate the specific roles of Family with sequence similarity 83 member H (FAM83H) in AI and determine its effect on ameloblasts. To investigate the impact of Fam83h on ameloblast gene expression, we utilized ameloblast line HAT-7 cells with knockdown of Fam83h gene for transcriptome sequencing. The experimental cell samples were undergone library preparation and RNA sequencing expreiments. Cell Adhesion test kit was employed to evaluate the influence of Fam83h on HAT-7 cell adhesion ability. RT-qPCR and western blot were conducted to analyze the expression levels of integrin and collagen proteins upon downregulation of Fam83h. RNA-seq analysis revealed differential expression of 572 genes in HAT-7 cells with knockdown of Fam83h gene, including 285 up-regulated genes and 287 down-regulated genes. GO and KEGG enrichment analysis indicated that Fam83h could modulate collagen synthesis in ameloblasts as well as affect the focal adhesion pathway. In the cell adhesion assay, we observed a decrease in adhesion ability due to downregulation of Fam83h in HAT-7 cell line. Furthermore, it was found that Fam83h can upregulated extracellular matrix collagen formation in ameloblasts. Fam83h may affect the adhesion ability and extracellular matrix collagen formation in ameloblasts, leading to AI.
2026-08-06 | Fam83h affected adhesion ability and extracellular matrix collagen formation in ameloblasts
Amelogenesis imperfecta (AI) is a group of inherited diseases characterized by enamel defects. Mutation in multiple genes may cause AI. The objective of this study was to investigate the specific roles of Family with sequence similarity 83 member H (FAM83H) in AI and determine its effect on ameloblasts. To investigate the impact of Fam83h on ameloblast gene expression, we utilized ameloblast line HAT-7 cells with knockdown of Fam83h gene for transcriptome sequencing. The experimental cell samples were undergone library preparation and RNA sequencing expreiments. Cell Adhesion test kit was employed to evaluate the influence of Fam83h on HAT-7 cell adhesion ability. RT-qPCR and western blot were conducted to analyze the expression levels of integrin and collagen proteins upon downregulation of Fam83h. RNA-seq analysis revealed differential expression of 572 genes in HAT-7 cells with knockdown of Fam83h gene, including 285 up-regulated genes and 287 down-regulated genes. GO and KEGG enrichment analysis indicated that Fam83h could modulate collagen synthesis in ameloblasts as well as affect the focal adhesion pathway. In the cell adhesion assay, we observed a decrease in adhesion ability due to downregulation of Fam83h in HAT-7 cell line. Furthermore, it was found that Fam83h can upregulated extracellular matrix collagen formation in ameloblasts. Fam83h may affect the adhesion ability and extracellular matrix collagen formation in ameloblasts, leading to AI.
2026-04-24 | Slc13a5 Expression in Ameloblast-Like Cells and Tooth Organ Cultures: A Platform for Therapeutic Studies
Mutations in SLC13A5, encoding the sodium-dependent citrate transporter (NaCT), cause developmental and epileptic encephalopathy 25 (DEE25), a disorder characterized by severe neurological impairment and enamel defects, including hypoplastic amelogenesis imperfecta. Although the neurological features of DEE25 are well documented, the mechanisms underlying enamel abnormalities remain poorly understood. In this study, we established in vitro and ex vivo systems to investigate NaCT function in enamel development and to support future gene therapy approaches. Mouse ameloblast-like LS8 cells were transfected with Slc13a5 expression plasmids to evaluate transfection efficiency, as well as gene and protein expression. Transient overexpression of Slc13a5 resulted in increased mRNA levels and detectable NaCT protein, with peak transcript expression at 48 hours and maximal protein and GFP reporter signal at 72 hours post- transfection. Immunocytochemistry further confirmed successful NaCT expression. To model enamel defects ex vivo, tooth organ cultures were established from wild-type and Slc13a5 R337*/R337* mouse molars. Mutant tooth germs in culture reproduced key pathological features observed in vivo, including irregular, ectopic mineral deposition. These findings demonstrate that the organ culture system can partially recapitulate the in vivo phenotype and serve as a platform for evaluating short-term gene delivery efficiency. Together, these results validate LS8 cells and tooth organ cultures as complementary platforms for studying Slc13a5 function and optimizing gene delivery strategies. This work provides a foundational step toward the development of adeno-associated virus (AAV)-based therapeutic approaches aimed at mitigating NaCT function and improving enamel defects associated with DEE25.
2026-03-07 | Generation and characterization of a murine amelogenesis imperfecta model.
Amelogenesis imperfecta (AI) refers to a group of rare yet complex genetic disorders that affect the quantity and/or quality of tooth enamel. Recently, in AI patients, we identified mutations that disrupt a conserved alternative splicing pattern of the AMELX gene, which encodes amelogenin, the most abundant enamel matrix protein. These mutations led to the retention of exon 4, which is normally skipped during the pre-mRNA splicing process, resulting in the characteristic pitted, hypoplastic, and hypomineralized enamel defects. To observe the impact of retention of exon 4 within AMELX, a gene edited knock-in mouse model was generated. A single-nucleotide knock-in mouse model was generated using CRISPR/Cas9 technology to introduce a silent mutation (NM_001415990.1: c.120 T>C, p.(Ala40=)) that abrogated alternative splicing of exon 4. Following genomic sequence validation, the successfully-targeted mice were propagated, and their offspring genotyped for characterization. Micro-computed tomography analysis and immunohistochemistry analysis were performed on the hemi-mandibles of the wild-type and the knock-in mice. The enamel of the knock-in mice was chalky white and lacked translucency, due to faulty mineralization. This defective enamel broke down soon after tooth eruption. During the maturation stage, the ameloblast layer lost its cellular polarity and homogeneity, and intermingled with adjacent cell types to form disorganized clusters. The validated and characterized Amelx c.120 T>C mouse model provides a useful platform for investigating the molecular pathophysiology associated with retention of the exon 4 sequence. Following systemic characterization, this mouse model will serve as an important tool for assessing therapeutic strategies aimed at ameliorating the disease phenotype.
2025-12-30 | Epidermolysis bullosa accompanied by amelogenesis imperfecta: A report of three cases and literature review
Introduction: Epidermolysis Bullosa (EB) is a group of genetic disorders characterized by skin and mucosal fragility. Similarly, Amelogenesis Imperfecta (AI) is a genetic condition that affects the development of dental enamel, leading to structural anomalies. Specific gene mutations, such as those affecting COL17A1, are known to cause both conditions, notably in patients with Junctional EB. This study explores the clinical presentations of three patients diagnosed with both AI and EB, with two cases confirmed to have COL17A1 mutations, linking the genetic mutation to both enamel defects and EBs. Case Reports: The clinical findings from three patients are reported. Two of the cases were diagnosed with Junctional EB, with genetic testing confirming COL17A1 mutations, which correlated with the presentation of hypoplastic enamel and pitting. All patients exhibited gingivitis and oral mucosal fragility, which posed challenges in maintaining oral hygiene. Discussion: Maintaining oral hygiene in patients with EB is particularly challenging due to the fragility of their oral mucosa. These challenges are exacerbated by the low socioeconomic status of the patients, limiting access to proper oral care tools. The study explores oral management strategies, including the use of soft toothbrushes, sucralfate for ulcer management, and the importance of a multidisciplinary approach. Regular dental check-ups and early intervention are emphasized as essential for improving patient outcomes and quality of life. Conclusion: It is crucial for dental practitioners to identify signs of AI in EB patients and to ensure timely referrals and consultations. Furthermore, EB patients should be referred to dental professionals early to prevent oral complications. A multidisciplinary approach is vital for addressing the complex needs of these patients effectively.
cell therapies
2024-06-25 | Protocol for generating three-dimensional induced early ameloblasts using serum-free media and growth factors.
Adult humans cannot regenerate the enamel-forming cell type, ameloblasts. Hence, human induced pluripotent stem cell (hiPSC)-derived ameloblasts are valuable for investigating tooth development and regeneration. Here, we present a protocol for generating three-dimensional induced early ameloblasts (ieAMs) utilizing serum-free media and growth factors. We describe steps for directing hiPSCs toward oral epithelium and then toward ameloblast fate. These cells can form suspended early ameloblast organoids. This approach is critical for understanding, treating, and promoting regeneration in diseases like amelogenesis imperfecta. For complete details on the use and execution of this protocol, please refer to Alghadeer et al.1.
2024-06-16 | Regenerative Endodontic Procedures in Immature Teeth Affected by Regional Odontodysplasia.
Regional odontodysplasia (ROD) is a rare developmental disorder characterized by hypo-mineralization and hypoplasia of enamel and dentin. Symptoms include poorly developed tooth buds, delayed eruption of permanent teeth in affected quadrants, and ghost teeth. The affected teeth often become necrotic due to abnormal enamel and dentin development, making them susceptible to caries and infection. The aim of this case report is to describe the treatment of ROD through pulp revascularization. A 13-year-old girl was referred for endodontic treatment. The mandibular left incisors and first premolar, which were affected by regional odontodysplasia, lost their vitality because of the impaired structure of the enamel. Due to the teeth's early developmental stage, a regenerative endodontic treatment was attempted. All 3 teeth were treated using the same protocol following the AAE guidelines. After 4 weeks, treatment of the premolar was completed, whereas the incisor teeth remained symptomatic and were and therefore, intracanal dressing with calcium hydroxide was repeated and left in place for 5 months. Finally, the regenerative procedure was completed, and the crowns were restored. The patient was scheduled for follow-up examinations after 6 months, and then yearly for the next 3 years. After 1 year, the periapical lesion around the central incisor and premolar had resolved, the lesion around the apex of the lateral incisor was healing, and the roots had continued to develop. After 3 years, complete healing and pulp canal obliteration were observed in the central incisor and in the premolar. However, the root of the lateral incisor tooth was split, and it was recommended to extract this tooth. The positive outcomes of regenerative endodontics in the central incisor and premolar suggest that revascularization of the pulp may be optional for the treatment of immature necrotic teeth affected by developmental disorders, such as ROD, amelogenesis imperfecta, or dentinogenesis imperfecta.
2024-03-18 | From Pluripotent Stem Cells to Organoids and Bioprinting: Recent Advances in Dental Epithelium and Ameloblast Models to Study Tooth Biology and Regeneration
Abstract Ameloblasts are the specialized dental epithelial cell type responsible for enamel formation. Following completion of enamel development in humans, ameloblasts are lost and biological repair or regeneration of enamel is not possible. In the past, in vitro models to study dental epithelium and ameloblast biology were limited to freshly isolated primary cells or immortalized cell lines, both with limited translational potential. In recent years, large strides have been made with the development of induced pluripotent stem cell and organoid models of this essential dental lineage – both enabling modeling of human dental epithelium. Upon induction with several different signaling factors (such as transforming growth factor and bone morphogenetic proteins) these models display elevated expression of ameloblast markers and enamel matrix proteins. The advent of 3D bioprinting, and its potential combination with these advanced cellular tools, is poised to revolutionize the field – and its potential for tissue engineering, regenerative and personalized medicine. As the advancements in these technologies are rapidly evolving, we evaluate the current state-of-the-art regarding in vitro cell culture models of dental epithelium and ameloblast lineage with a particular focus toward their applicability for translational tissue engineering and regenerative/personalized medicine. Graphical Abstract Future perspectives for in vitro modeling of dental epithelium and ameloblasts. Development of iPSC and organoid models that can reliably generate dental epithelium and ameloblast-like cells, together with advances in 3D bioprinting, provide promising tools for enamel research. Advanced models will provide new avenues for development of enamel repair/regeneration approaches, for testing of dental materials or drugs, studying host-pathogen and/or cell-cell interactions, in vitro modeling of enamel diseases (e.g. amelogenesis imperfecta) and developing novel insights in fundamental tooth biology (e.g. regulation of amelogenesis, lineage specification). Abbreviations: iPSC: induced pluripotent stem cells; TO: tooth organoids; DE: dental epithelium; AB: ameloblast.
2023-11-07 | Single-cell census of human tooth development enables generation of human enamel.
Tooth enamel secreted by ameloblasts (AMs) is the hardest material in the human body, acting as a shield to protect the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here, we use single-cell combinatorial indexing RNA sequencing (sci-RNA-seq) to establish a spatiotemporal single-cell census for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We identify key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in human ameloblast in vitro differentiation from induced pluripotent stem cells (iPSCs). We furthermore develop a disease model of amelogenesis imperfecta in a three-dimensional (3D) organoid system and show AM maturation to mineralized structure in vivo. These studies pave the way for future regenerative dentistry.
2021-07-03 | Stage-Specific Role of Amelx Activation in Stepwise Ameloblast Induction from Mouse Induced Pluripotent Stem Cells
Amelogenin comprises ~90% of enamel proteins; however, the involvement of Amelx transcriptional activation in regulating ameloblast differentiation from induced pluripotent stem cells (iPSCs) remains unknown. In this study, we generated doxycycline-inducible Amelx-expressing mouse iPSCs (Amelx-iPSCs). We then established a three-stage ameloblast induction strategy from Amelx-iPSCs, including induction of surface ectoderm (stage 1), dental epithelial cells (DECs; stage 2), and ameloblast lineage (stage 3) in sequence, by manipulating several signaling molecules. We found that adjunctive use of lithium chloride (LiCl) in addition to bone morphogenetic protein 4 and retinoic acid promoted concentration-dependent differentiation of DECs. The resulting cells had a cobblestone appearance and keratin14 positivity. Attenuation of LiCl at stage 3 together with transforming growth factor β1 and epidermal growth factor resulted in an ameloblast lineage with elongated cell morphology, positivity for ameloblast markers, and calcium deposition. Although stage-specific activation of Amelx did not produce noticeable phenotypic changes in ameloblast differentiation, Amelx activation at stage 3 significantly enhanced cell adhesion as well as decreased proliferation and migration. These results suggest that the combination of inducible Amelx transcription and stage-specific ameloblast induction for iPSCs represents a powerful tool to highlight underlying mechanisms in ameloblast differentiation and function in association with Amelx expression.
other
2023-03-07 | Amelogenesis imperfecta in a Chinese family resulting from a FAM83H variation and the effect of FAM83H on the secretion of enamel matrix proteins.
To investigate the variant of an amelogenesis imperfecta (AI) family and to explore the function of the FAM83H (family with sequence similarity 83 member H) in the enamel formation. We investigated a five-generation Chinese family diagnosed with AI; clinical data was collected, whole-exome sequencing (WES) was conducted to explore the pathogenic gene and variants and Sanger sequencing was used to verify the variants. The three-dimensional protein structures of wild-type and mutant FAM83H were predicted using alpha fold 2. To study the possible regulatory function of Fam83h on amelogenesis, immunolocalization was performed to observe the expression of Fam83h protein in Sprague-Dawley rat postnatal incisors. The mRNA and protein level of amelogenin, enamelin, kallikrein-related peptidase-4 and ameloblastin were also detected after the Fam83h was knocked down by small interfering RNA (siRNA) in HAT-7 cells. A known nonsense variant (c.973 C > T) in exon 5 of FAM83H gene was found in this family, causing a truncated protein (p.R325X). Immunolocalization of Fam83h in Sprague-Dawley rat postnatal incisors showed that Fam83h protein expression was detected in presecretory and secretory stages. When Fam83h expression was reduced by siRNA, the expression of amelogenin, enamelin, kallikrein-related peptidase-4 decreased. However, the expression of ameloblastin increased. FAM83H gene variant (c.973 C > T) causes AI. FAM83H regulates the secretion of enamel matrix proteins and affects ameloblast differentiation. This study provided that FAM83H variants could influence enamel formation and provided new insights into the pathogenesis of AI.
2022-11-17 | N6-methyladenosine (m6A) RNA methylation mediated by methyltransferase complex subunit WTAP regulates amelogenesis
N6-methyladenosine (m6A) RNA methylation, one of the most widespread posttranscriptional modifications in eukaryotes, plays crucial roles in various developmental processes. The m6A modification process is catalyzed by a methyltransferase complex that includes Wilms tumor 1-associated protein (WTAP) as a key component. Whether the development of dental enamel is regulated by m6A RNA methylation in mammals remains unclear. Here, we reveal that WTAP is widely expressed from the early stage of tooth development. Specific inactivation of Wtap in mouse enamel epithelium by the Cre/loxp system leads to serious developmental defects in amelogenesis. In Wtap conditional KO mice, we determined that the differentiation of enamel epithelial cells into mature ameloblasts at the early stages of enamel development is affected. Mechanistically, loss of Wtap inhibits the expression of Sonic hedgehog (SHH), which plays an important role in the generation of ameloblasts from stem cells. Together, our findings provide new insights into the functional role of WTAP-mediated m6A methylation in amelogenesis in mammals.
2022-07-26 | MiR-148a-3p Regulates Stem Cell Osteogenic Differentiation and Enamel Development by Targeting Runt-Related Transcription Factor 2 and E-cadherin <i>via</i> the Wnt1/β-catenin Signaling Pathway
We aimed to evaluate the regulatory effects of miR-148a-3p on stem cell osteogenic differentiation and enamel development by targeting runt-related transcription factor 2 (RUNX2) and E-cadherin, respectively. TargetScan software was utilized to predict the binding sites between miR-148a-3p and osteogenic marker gene RUNX2 or E-cadherin. The changes in miR-148a-3p expression during osteogenic differentiation of epidermal stem cells were detected. After transfection with miR-148a-3p mimics or miR-148a-3p inhibitor, epidermal stem cells were induced towards osteogenic differentiation, and the changes in RUNX2 expression were measured. The changes in miR-148a-3p expression during enamel development regulated by epidermal stem cells were determined. After liposome-mediated transfection with miR-148a-3p mimics or miR-148a-3p inhibitor, epidermal stem cells were induced towards ameloblast development. Cell proliferation and apoptosis abilities were tested using methyl thiazolyl tetrazolium assay and flow cytometry, respectively. The expression of miR-148a-3p was detected by RT-PCR. The protein expressions of Wnt1, β-catenin, RUNX2 and E-cadherin were measured by Western blotting. Epidermal stem cells differentiated into osteoblasts through osteogenic induction culture. On 5, 12, 15 and 30 d, epidermal stem cells gradually differentiated into osteoblasts through epithelial aggregation and depression, mesenchymal aggregation, and dentin and enamel secretion. After transfection, compared with negative control (NC) group, the cell viability of miR-148-3p group significantly decreased (P<0.05), and the apoptosis rate increased (P<0.01). The viability of miR-148-3p inhibitor group significantly increased (P<0.05), while the apoptosis rate reduced (P<0.01). The dual-luciferase reporter assay showed that miR-148a-3p targeted Wnt1. Compared with NC group, the expression of miR-148a-3p significantly rose in miR-148a-3p group (P<0.001), and the protein expression levels of Wnt1, β-catenin, RUNX2 and E-cadherin significantly decreased. Compared with NC group, the expression of miR-148a-3p in miR-148a-3p inhibitor group significantly decreased (P<0.05), and the protein expression levels of Wnt1, β-catenin, RUNX2 and E-cadherin significantly increased. MiR-148a-3p is highly expressed in and regulates osteogenic differentiation and enamel development through targeting RUNX2 and E-cadherin respectively via the Wnt1/β-catenin pathway, which plays an important role in cell differentiation, stem cell proliferation and enamel development.
2021-06-01 | Overexpression of miR-1306-5p, miR-3195, and miR-3914 Inhibits Ameloblast Differentiation through Suppression of Genes Associated with Human Amelogenesis Imperfecta.
Amelogenesis imperfecta is a congenital form of enamel hypoplasia. Although a number of genetic mutations have been reported in humans, the regulatory network of these genes remains mostly unclear. To identify signatures of biological pathways in amelogenesis imperfecta, we conducted bioinformatic analyses on genes associated with the condition in humans. Through an extensive search of the main biomedical databases, we found 56 genes in which mutations and/or association/linkage were reported in individuals with amelogenesis imperfecta. These candidate genes were further grouped by function, pathway, protein-protein interaction, and tissue-specific expression patterns using various bioinformatic tools. The bioinformatic analyses highlighted a group of genes essential for extracellular matrix formation. Furthermore, advanced bioinformatic analyses for microRNAs (miRNAs), which are short non-coding RNAs that suppress target genes at the post-transcriptional level, predicted 37 candidates that may be involved in amelogenesis imperfecta. To validate the miRNA-gene regulation association, we analyzed the target gene expression of the top seven candidate miRNAs: miR-3195, miR-382-5p, miR-1306-5p, miR-4683, miR-6716-3p, miR-3914, and miR-3935. Among them, miR-1306-5p, miR-3195, and miR-3914 were confirmed to regulate ameloblast differentiation through the regulation of genes associated with amelogenesis imperfecta in AM-1 cells, a human ameloblastoma cell line. Taken together, our study suggests a potential role for miRNAs in amelogenesis imperfecta.
2017-03-13 | MiR-153 Regulates Amelogenesis by Targeting Endocytotic and Endosomal/lysosomal Pathways–Novel Insight into the Origins of Enamel Pathologies
Abstract Amelogenesis imperfecta (AI) is group of inherited disorders resulting in enamel pathologies. The involvement of epigenetic regulation in the pathogenesis of AI is yet to be clarified due to a lack of knowledge about amelogenesis. Our previous genome-wide microRNA and mRNA transcriptome analyses suggest a key role for miR-153 in endosome/lysosome-related pathways during amelogenesis. Here we show that miR-153 is significantly downregulated in maturation ameloblasts compared with secretory ameloblasts. Within ameloblast-like cells, upregulation of miR-153 results in the downregulation of its predicted targets including Cltc, Lamp1, Clcn4 and Slc4a4, and a number of miRNAs implicated in endocytotic pathways. Luciferase reporter assays confirmed the predicted interactions between miR-153 and the 3′-UTRs of Cltc, Lamp1 (in a prior study), Clcn4 and Slc4a4. In an enamel protein intake assay, enamel cells transfected with miR-153 show a decreased ability to endocytose enamel proteins. Finally, microinjection of miR-153 in the region of mouse first mandibular molar at postnatal day 8 (PN8) induced AI-like pathologies when the enamel development reached maturity (PN12). In conclusion, miR-153 regulates maturation-stage amelogenesis by targeting key genes involved in the endocytotic and endosomal/lysosomal pathways, and disruption of miR-153 expression is a potential candidate etiologic factor contributing to the occurrence of AI.
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Drug Discovery Landscape
1 orphan drug designation for Amelogenesis imperfecta.
1 orphan drug designation for Amelogenesis imperfecta.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Copine7-derived peptide | peptides | FDA | 2024-12-09 | — | HysensBio Co., Ltd. |
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