-
Journal of Dental Research Aug 2023Tooth enamel is generated by ameloblasts. Any failure in amelogenesis results in defects in the enamel, a condition known as amelogenesis imperfecta. Here, we report...
Tooth enamel is generated by ameloblasts. Any failure in amelogenesis results in defects in the enamel, a condition known as amelogenesis imperfecta. Here, we report that mice with deficient autophagy in epithelial-derived tissues ( and conditional knockout mice) exhibit amelogenesis imperfecta. Micro-computed tomography imaging confirmed that enamel density and thickness were significantly reduced in the teeth of these mice. At the molecular level, ameloblast differentiation was compromised through ectopic accumulation and activation of NRF2, a specific substrate of autophagy. Through bioinformatic analyses, we identified , , , , , and as candidate genes related to amelogenesis imperfecta and the NRF2-mediated pathway. To investigate the effects of the ectopic NRF2 pathway activation caused by the autophagy deficiency, we analyzed target gene expression and NRF2 binding to the promoter region of candidate target genes and found suppressed gene expression of , , , and but not of and . Taken together, our findings indicate that autophagy plays a crucial role in ameloblast differentiation and that its failure results in amelogenesis imperfecta through ectopic NRF2 activation.
Topics: Mice; Animals; Ameloblasts; Amelogenesis Imperfecta; X-Ray Microtomography; NF-E2-Related Factor 2; Amelogenesis; Mice, Knockout; Tumor Suppressor Proteins; Repressor Proteins
PubMed: 37249312
DOI: 10.1177/00220345231169220 -
Cureus Dec 2023Amelogenesis imperfecta (AI) is a rare genetic disorder affecting children and adults. Knowledge about AI is limited to clinical representation and radiographical... (Review)
Review
Amelogenesis imperfecta (AI) is a rare genetic disorder affecting children and adults. Knowledge about AI is limited to clinical representation and radiographical findings. Various treatments are provided to children with AI, yet no definitive treatment guideline has been suggested in the literature. This scoping review highlights the knowledge of the etiology and classification of AI and synthesizes these findings in a comprehensive review, focusing mainly on the various forms of AI in children and management with a restorative conservative approach. Five electronic databases, namely, PubMed, Google Scholar, Embase, Web of Science, and Scopus, were searched for the relevant articles. The search was performed in two phases: first for title and abstract, and second for full-text articles. The studies included in this scoping review were published from 2013 to August 2023. The data extraction was done on a customized sheet. A total of 33 studies were included in this review, of which 19 were reports and series, seven were observational, and seven were reviews. Most patients included in this review suffered from the hypoplastic type of AI (54%), followed by hypomatured (36%), and hypocalcified (10%). The treatment modalities explained were divided into the following three phases: temporary, transient, and permanent. Almost all included reports suggested the requirement for guidelines for treating AI among young children. This scoping review suggests the need for guidelines for treating AI in children. Moreover, pediatric dentists should prioritize early diagnosis and treatment and long-term follow-up for AI in children to effectively enhance the patient's psychological well-being and overall quality of life.
PubMed: 38179349
DOI: 10.7759/cureus.49968 -
Journal of Dental Research Oct 2023Amelogenin plays a crucial role in tooth enamel formation, and mutations on X-chromosomal amelogenin cause X-linked amelogenesis imperfecta (AI). Amelogenin...
Amelogenin plays a crucial role in tooth enamel formation, and mutations on X-chromosomal amelogenin cause X-linked amelogenesis imperfecta (AI). Amelogenin pre-messenger RNA (mRNA) is highly alternatively spliced, and during alternative splicing, exon4 is mostly skipped, leading to the formation of a microRNA (miR-exon4) that has been suggested to function in enamel and bone formation. While delivering the functional variation of amelogenin proteins, alternative splicing of exon4 is the decisive first step to producing miR-exon4. However, the factors that regulate the splicing of exon4 are not well understood. This study aimed to investigate the association between known mutations in exon4 and exon5 of X chromosome amelogenin that causes X-linked AI, the splicing of exon4, and miR-exon4 formation. Our results showed mutations in exon4 and exon5 of the amelogenin gene, including c.120T>C, c.152C>T, c.155C>G, and c.155delC, significantly affected the splicing of exon4 and subsequent miR-exon4 production. Using an amelogenin minigene transfected in HEK-293 cells, we observed increased inclusion of exon4 in amelogenin mRNA and reduced miR-exon4 production with these mutations. In silico analysis predicted that Ser/Arg-rich RNA splicing factor (SRSF) 2 and SRSF5 were the regulatory factors for exon4 and exon5 splicing, respectively. Electrophoretic mobility shift assay confirmed that SRSF2 binds to exon4 and SRSF5 binds to exon5, and mutations in each exon can alter SRSF binding. Transfection of the amelogenin minigene to LS8 ameloblastic cells suppressed expression of the known miR-exon4 direct targets, and , related to multiple pathways. Given the mutations on the minigene, the expression of has been significantly upregulated with c.155C>G and c.155delC mutations. Together, we confirmed that exon4 splicing is critical for miR-exon4 production, and mutations causing X-linked AI in exon4 and exon5 significantly affect exon4 splicing and following miR-exon4 production. The change in miR-exon4 would be an additional etiology of enamel defects seen in some X-linked AI.
Topics: Humans; Amelogenin; Amelogenesis Imperfecta; HEK293 Cells; Mutation; Dental Enamel Proteins; MicroRNAs; RNA, Messenger
PubMed: 37563801
DOI: 10.1177/00220345231180572 -
Revista Cientifica Odontologica... 2023The main origin of amelogenesis imperfecta (AI) is a genetic alteration inherited by a family member which affects the dental enamel of the teeth of a person with this...
The main origin of amelogenesis imperfecta (AI) is a genetic alteration inherited by a family member which affects the dental enamel of the teeth of a person with this condition in various ways. The present clinical case from the Teaching Dental Clinic of the Peruvian University Cayetano Heredia is of a 6-year 5-month-old male child who came to the dental office accompanied by his father and 8-year-old sister, diagnosed with the same AI condition. The comprehensive treatment proposed for this patient was determined by radiographic and clinical examinations and consultations with specialists in different areas. The purpose of this publication was to report a case and describe possible clinical approaches.
PubMed: 38288452
DOI: 10.21142/2523-2754-1102-2023-156 -
Journal of Dentistry Jun 2024To summarize studies published between 2017 and 2023 examining the clinical diagnosis and restorative management of amelogenesis imperfecta (AI) in children and... (Review)
Review
OBJECTIVE
To summarize studies published between 2017 and 2023 examining the clinical diagnosis and restorative management of amelogenesis imperfecta (AI) in children and adolescents.
DATA
The review incorporated publications on clinical diagnosis, patient-reported outcomes, clinical trials, cohort studies, and case reports that included individuals below 19 years of age with non-syndromic AI.
SOURCES
A literature search was conducted across electronic databases, PubMed, Web of Science, and CINAHL, including papers published between 2017-2023. The search yielded 335 unique results, of which 38 were eligible for inclusion.
RESULTS
New evidence on the genetic background of AI makes it now advisable to recommend genetic testing to supplement a clinical AI diagnosis. The discussions of the dental profession and the public on social media do not always incorporate recent scientific evidence. Interview studies are finding that the impact of AI on quality of life is more severe than previously appreciated. New evidence suggests that single-tooth ceramic crowns should be the first choice of treatment. Due to incomplete reporting, case reports have been of limited value.
CONCLUSION
In young patients with AI symptoms of pain and hypersensitivity decreased, and aesthetics were improved following all types of restorative therapy. Resin composite restorations were mainly performed in cases with hypoplastic AI and mild symptoms. Single tooth ceramic crown restorations have a high success rate in all types of AI and can be used in young individuals with AI.
CLINICAL SIGNIFICANCE
Prosthetic rehabilitation in adolescents with severe AI is cost effective, improves esthetics, reduces tooth sensitivity, and improves oral health-related quality of life.
PubMed: 38909645
DOI: 10.1016/j.jdent.2024.105149 -
International Journal of Oral Science Dec 2023Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated...
Ameloblasts are specialized cells derived from the dental epithelium that produce enamel, a hierarchically structured tissue comprised of highly elongated hydroxylapatite (OHAp) crystallites. The unique function of the epithelial cells synthesizing crystallites and assembling them in a mechanically robust structure is not fully elucidated yet, partly due to limitations with in vitro experimental models. Herein, we demonstrate the ability to generate mineralizing dental epithelial organoids (DEOs) from adult dental epithelial stem cells (aDESCs) isolated from mouse incisor tissues. DEOs expressed ameloblast markers, could be maintained for more than five months (11 passages) in vitro in media containing modulators of Wnt, Egf, Bmp, Fgf and Notch signaling pathways, and were amenable to cryostorage. When transplanted underneath murine kidney capsules, organoids produced OHAp crystallites similar in composition, size, and shape to mineralized dental tissues, including some enamel-like elongated crystals. DEOs are thus a powerful in vitro model to study mineralization process by dental epithelium, which can pave the way to understanding amelogenesis and developing regenerative therapy of enamel.
Topics: Mice; Animals; Durapatite; Dental Enamel; Ameloblasts; Amelogenesis; Stem Cells; Organoids
PubMed: 38062012
DOI: 10.1038/s41368-023-00257-w -
Oral Diseases Nov 2023Amelogenesis imperfecta (AI) is defined as inherited enamel malformations. LAMA3 (laminin alpha-3) encodes a critical protein component of the basement membrane...
OBJECTIVE
Amelogenesis imperfecta (AI) is defined as inherited enamel malformations. LAMA3 (laminin alpha-3) encodes a critical protein component of the basement membrane (laminin-332). Individuals carrying heterozygous LAMA3 mutations have previously been shown to have localized enamel defects. This study aimed to define clinical phenotypes and to discern the genetic etiology for four AI kindreds.
MATERIALS AND METHODS
Whole-exome analyses were conducted to search for sequence variants associated with the disorder, and micro-computed tomography (μCT) to characterize the enamel defects.
RESULTS
The predominant enamel phenotype was generalized thin enamel with defective pits and grooves. Horizonal bands of hypoplastic enamel with chalky-white discoloration and enamel hypomineralization were also observed and demonstrated by μCT analyses of affected teeth. Four disease-causing LAMA3 mutations (NM_198129.4:c.3712dup; c.5891dup; c.7367del; c.9400G > C) were identified. Compound heterozygous MMP20 mutations (NM_004771.4:c.539A > G; c.692C > T) were also found in one proband with more severe enamel defects, suggesting a mutational synergism on disease phenotypes. Further analyses of the AI-causing mutations suggested that both α3A (short) and α3B (long) isoforms of LAMA3 are essential for enamel formation.
CONCLUSIONS
Heterozygous LAMA3 mutations can cause generalized enamel defects (AI1A) with variable expressivity. Laminin-332 is critical not only for appositional growth but also enamel maturation.
Topics: Humans; Amelogenesis Imperfecta; Laminin; X-Ray Microtomography; Dental Enamel; Extracellular Matrix Proteins; Mutation; Phenotype; Biological Variation, Population; Pedigree
PubMed: 36326426
DOI: 10.1111/odi.14425 -
Journal of Dental Research Jan 2024Amelogenesis imperfecta (AI) comprises a group of rare, inherited disorders with abnormal enamel formation. Ameloblastin (AMBN), the second most abundant enamel matrix...
Amelogenesis imperfecta (AI) comprises a group of rare, inherited disorders with abnormal enamel formation. Ameloblastin (AMBN), the second most abundant enamel matrix protein (EMP), plays a critical role in amelogenesis. Pathogenic biallelic loss-of-function variants are known to cause recessive hypoplastic AI. A report of a family with dominant hypoplastic AI attributed to AMBN missense change p.Pro357Ser, together with data from animal models, suggests that the consequences of variants in human AI remain incompletely characterized. Here we describe 5 new pathogenic variants in 11 individuals with AI. These fall within 3 groups by phenotype. Group 1, consisting of 6 families biallelic for combinations of 4 different variants, have yellow hypoplastic AI with poor-quality enamel, consistent with previous reports. Group 2, with 2 families, appears monoallelic for a variant shared with group 1 and has hypomaturation AI of near-normal enamel volume with pitting. Group 3 includes 3 families, all monoallelic for a fifth variant, which are affected by white hypoplastic AI with a thin intact enamel layer. Three variants, c.209C>G; p.(Ser70*) (groups 1 and 2), c.295T>C; p.(Tyr99His) (group 1), and c.76G>A; p.(Ala26Thr) (group 3) were identified in multiple families. Long-read locus sequencing revealed these variants are on the same conserved haplotype, implying they originate from a common ancestor. Data presented therefore provide further support for possible dominant as well as recessive inheritance for -related AI and for multiple contrasting phenotypes. In conclusion, our findings suggest pathogenic variants have a more complex impact on human AI than previously reported.
Topics: Animals; Humans; Amelogenesis; Amelogenesis Imperfecta; Dental Enamel Proteins; Pedigree; Phenotype
PubMed: 38058155
DOI: 10.1177/00220345231203694 -
Frontiers in Physiology 2023
PubMed: 38028793
DOI: 10.3389/fphys.2023.1323504