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:
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.
2026-07-13 | 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.
2026-08-06 | 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.
2026-07-13 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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