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Molecular Genetics & Genomic Medicine Oct 2019ENAM mutations cause autosomal dominant or recessive amelogenesis imperfecta (AI) and show a dose effect: enamel malformations are more severe or only penetrant when...
BACKGROUND
ENAM mutations cause autosomal dominant or recessive amelogenesis imperfecta (AI) and show a dose effect: enamel malformations are more severe or only penetrant when both ENAM alleles are defective.
METHODS
Whole exome sequences of recruited AI probands were initially screened for mutations in known AI candidate genes. Sanger sequencing was used to confirm sequence variations and their segregation with the disease phenotype. The co-occurrence of ENAM and LAMA3 mutations in one family raised the possibility of digenic inheritance. Enamel formed in Enam Ambn , Enam , Ambn , and Enam Ambn mice was characterized by dissection and backscattered scanning electron microscopy (bSEM).
RESULTS
ENAM mutations segregating with AI in five families were identified. Two novel ENAM frameshift mutations were identified. A single-nucleotide duplication (c.395dupA/p.Pro133Alafs*13) replaced amino acids 133-1142 with a 12 amino acid (ATTKAAFEAAIT*) sequence, and a single-nucleotide deletion (c.2763delT/p.Asp921Glufs*32) replaced amino acids 921-1142 with 31 amino acids (ESSPQQASYQAKETAQRRGKAKTLLEMMCPR*). Three families were heterozygous for a previously reported single-nucleotide ENAM deletion (c.588+1delG/p.Asn197Ilefs*81). One of these families also harbored a heterozygous LAMA3 mutation (c.1559G>A/p.Cys520Tyr) that cosegregated with both the AI phenotype and the ENAM mutation. In mice, Ambn maxillary incisors were normal. Ambn molars were also normal, except for minor surface roughness. Ambn mandibular incisors were sometimes chalky and showed minor chipping. Enam incisor enamel was thinner than normal with ectopic mineral deposited laterally. Enam molars were sometimes chalky and rough surfaced. Enam Ambn enamel was thin and rough, in part due to ectopic mineralization, but also underwent accelerated attrition.
CONCLUSION
Novel ENAM mutations causing AI were identified, raising to 22 the number of ENAM variations known to cause AI. The severity of the enamel phenotype in Enam Ambn double heterozygous mice is caused by composite digenic effects. Digenic inheritance should be explored as a cause of AI in humans.
Topics: Amelogenesis Imperfecta; Extracellular Matrix Proteins; Female; Frameshift Mutation; Gene Deletion; Heterozygote; Humans; Laminin; Male; Pedigree; Phenotype; Polymorphism, Single Nucleotide; Exome Sequencing
PubMed: 31478359
DOI: 10.1002/mgg3.928 -
Journal of Prosthodontics : Official... Aug 2018To summarize the contemporary scientific evidence available regarding restorative dental treatment in patients with Amelogenesis imperfecta (AI). (Review)
Review
PURPOSE
To summarize the contemporary scientific evidence available regarding restorative dental treatment in patients with Amelogenesis imperfecta (AI).
METHODS
An electronic literature search was conducted using the search term "Amelogenesis imperfecta" and the PubMed/MEDLINE database as well as Google Scholar. Prospective and retrospective clinical studies that investigated the outcome of direct and/or indirect dental restorative treatment in patients with AI, were published in English, and had an observation time of at least 1 year were included in this review. The articles identified were screened and analyzed by two reviewers according to inclusion and exclusion criteria in three review rounds.
RESULTS
Six prospective or retrospective clinical studies analyzing longevity and complications associated with dental restorative treatment in patients with AI met the inclusion criteria. Extracted data suggest that in patients with AI, indirect restorations feature superior predictability and longevity than direct restorations.
CONCLUSIONS
As endodontic complications were infrequently observed and periodontal parameters regularly improve with the insertion of indirect restorations, dental treatment in patients with AI should focus on indirect restorations as soon as possible. While adhesive bonding techniques to enamel surfaces in patients with AI feature merely limited predictability and longevity and as the available data is scarce, further laboratory and clinical studies should be performed to investigate the performance of minimally invasive indirect restorations bonded to enamel in patients with AI.
RECOMMENDATION
Scientific evidence indicates that indirect restorations should be preferred over direct restorations in patients with AI.
Topics: Amelogenesis Imperfecta; Dental Restoration, Permanent; Humans
PubMed: 29377372
DOI: 10.1111/jopr.12736 -
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 Structural Biology Dec 2021During enamel formation, the organic enamel protein matrix interacts with calcium phosphate minerals to form elongated, parallel, and bundled enamel apatite crystals of... (Review)
Review
During enamel formation, the organic enamel protein matrix interacts with calcium phosphate minerals to form elongated, parallel, and bundled enamel apatite crystals of extraordinary hardness and biomechanical resilience. The enamel protein matrix consists of unique enamel proteins such as amelogenin, ameloblastin, and enamelin, which are secreted by highly specialized cells called ameloblasts. The ameloblasts also facilitate calcium and phosphate ion transport toward the enamel layer. Within ameloblasts, enamel proteins are transported as a polygonal matrix with 5 nm subunits in secretory vesicles. Upon expulsion from the ameloblasts, the enamel protein matrix is re-organized into 20 nm subunit compartments. Enamel matrix subunit compartment assembly and expansion coincide with C-terminal cleavage by the MMP20 enamel protease and N-terminal amelogenin self-assembly. Upon enamel crystal precipitation, the enamel protein phase is reconfigured to surround the elongating enamel crystals and facilitate their elongation in C-axis direction. At this stage of development, and upon further amelogenin cleavage, central and polyproline-rich fragments of the amelogenin molecule associate with the growing mineral crystals through a process termed "shedding", while hexagonal apatite crystals fuse in longitudinal direction. Enamel protein sheath-coated enamel "dahlite" crystals continue to elongate until a dense bundle of parallel apatite crystals is formed, while the enamel matrix is continuously degraded by proteolytic enzymes. Together, these insights portrait enamel mineral nucleation and growth as a complex and dynamic set of interactions between enamel proteins and mineral ions that facilitate regularly seeded apatite growth and parallel enamel crystal elongation.
Topics: Ameloblasts; Amelogenesis; Amelogenin; Animals; Apatites; Calcium; Calcium Phosphates; Crystallization; Dental Enamel; Dental Enamel Proteins; Humans; Microscopy, Electron; Minerals
PubMed: 34748943
DOI: 10.1016/j.jsb.2021.107809 -
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 -
Matrix Biology : Journal of the... 2016Amelotin (AMTN) and kallikrein-4 (KLK4) are secreted proteins specialized for enamel biomineralization. We characterized enamel from wild-type, Amtn(-/-), Klk4(-/-),... (Review)
Review
Amelotin (AMTN) and kallikrein-4 (KLK4) are secreted proteins specialized for enamel biomineralization. We characterized enamel from wild-type, Amtn(-/-), Klk4(-/-), Amtn(+/-)Klk4(+/-) and Amtn(-/-)Klk4(-/-) mice to gain insights into AMTN and KLK4 functions during amelogenesis. All of the null mice were healthy and fertile. The mandibular incisors in Amtn(-/-), Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice were chalky-white and chipped. No abnormalities except in enamel were observed, and no significant differences were detected in enamel thickness or volume, or in rod decussation. Micro-computed tomography (μCT) maximum intensity projections localized the onset of enamel maturation in wild-type incisors distal to the first molar, but mesial to this position in Amtn(-/-), Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice, demonstrating a delay in enamel maturation in Amtn(-/-) incisors. Micro-CT detected significantly reduced enamel mineral density (2.5 and 2.4gHA/cm(3)) in the Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice respectively, compared with wild-type enamel (3.1gHA/cm(3)). Backscatter scanning electron microscopy showed that mineral density progressively diminished with enamel depth in the Klk4(-/-) and Amtn(-/-)Klk4(-/-) mice. The Knoop hardness of the Amtn(-/-) outer enamel was significantly reduced relative to the wild-type and was not as hard as the middle or inner enamel. Klk4(-/-) enamel hardness was significantly reduced at all levels, but the outer enamel was significantly harder than the inner and middle enamel. Thus the hardness patterns of the Amtn(-/-) and Klk4(-/-) mice were distinctly different, while the Amtn(-/-)Klk4(-/-) outer enamel was not as hard as in the Amtn(-/-) and Klk4(-/-) mice. We conclude that AMTN and KLK4 function independently, but are both necessary for proper enamel maturation.
Topics: Amelogenesis; Animals; Dental Enamel; Dental Enamel Proteins; Incisor; Kallikreins; Mice; Mice, Knockout; Microscopy, Electron, Scanning; Molar; Tooth Calcification; X-Ray Microtomography
PubMed: 26620968
DOI: 10.1016/j.matbio.2015.11.007 -
Journal of Structural Biology Dec 2021The revolution in genetics has rapidly increased our knowledge of human and mouse genes that are critical for the formation of dental enamel and helps us understand how... (Review)
Review
The revolution in genetics has rapidly increased our knowledge of human and mouse genes that are critical for the formation of dental enamel and helps us understand how enamel evolved. In this graphical review we focus on the roles of 41 genes that are essential for the secretory stage of amelogenesis when characteristic enamel mineral ribbons initiate on dentin and elongate to expand the enamel layer to the future surface of the tooth. Based upon ultrastructural analyses of genetically modified mice, we propose a molecular model explaining how a cell attachment apparatus including collagen 17, α6ß4 and αvß6 integrins, laminin 332, and secreted enamel proteins could attach to individual enamel mineral ribbons and mold their cross-sectional dimensions as they simultaneously elongate and orient them in the direction of the retrograde movement of the ameloblast membrane.
Topics: Ameloblasts; Amelogenesis; Animals; Collagen; Dental Enamel; Dental Enamel Proteins; Humans; Integrins; Laminin; Mice; Microscopy, Electron, Scanning; Models, Genetic
PubMed: 34715329
DOI: 10.1016/j.jsb.2021.107805 -
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 -
Journal of Dental Research Jan 2015The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue... (Review)
Review
The formation of human enamel is highly regulated at the molecular level and involves thousands of genes. Requisites for development of this highly mineralized tissue include cell differentiation; production of a unique extracellular matrix; processing of the extracellular matrix; altering of cell function during different stages of enamel formation; cell movement and attachment; regulation of ion and protein movement; and regulation of hydration, pH, and other conditions of the microenvironment, to name just a few. Not surprising, there is a plethora of hereditary conditions with an enamel phenotype. The objective of this review was to identify the hereditary conditions listed on Online Mendelian Inheritance in Man (OMIM) that have an associated enamel phenotype and whether a causative gene has been identified. The OMIM database was searched with the terms amelogenesis, enamel, dental, and tooth, and all results were screened by 2 individuals to determine if an enamel phenotype was identified. Gene and gene product function was reviewed on OMIM and from publications identified in PubMed. The search strategy revealed 91 conditions listed in OMIM as having an enamel phenotype, and of those, 71 have a known molecular etiology or linked genetic loci. The purported protein function of those conditions with a known genetic basis included enzymes, regulatory proteins, extracellular matrix proteins, transcription factors, and transmembrane proteins. The most common enamel phenotype was a deficient amount of enamel, or enamel hypoplasia, with hypomineralization defects being reported less frequently. Knowing these molecular defects allows an initial cataloging of molecular pathways that lead to hereditary enamel defects in humans. This knowledge provides insight into the diverse molecular pathways involved in enamel formation and can be useful when searching for the genetic etiology of hereditary conditions that involve enamel.
Topics: Amelogenesis; Databases, Genetic; Dental Enamel; Dental Enamel Hypoplasia; Dental Enamel Proteins; Humans; Phenotype
PubMed: 25389004
DOI: 10.1177/0022034514556708 -
Matrix Biology : Journal of the... 2016Several diseases such as proximal and distal renal tubular acidosis and osteoporosis are related to intracellular pH dysregulation resulting from mutations in genes... (Review)
Review
Several diseases such as proximal and distal renal tubular acidosis and osteoporosis are related to intracellular pH dysregulation resulting from mutations in genes coding for ion channels, including proteins comprising the proton-pumping V-type ATPase. V-type ATPase is a multi-subunit protein complex expressed in enamel forming cells. V-type ATPase plays a key role in enamel development, specifically lysosomal acidification, yet our understanding of the relationship between the endocytotic activities and dental health and disease is limited. The objective of this study is to better understand the ameloblast-associated pH regulatory networks essential for amelogenesis. Quantitative RT-PCR was performed on tissues from secretory-stage and maturation-stage enamel organs to determine which of the V-type ATPase subunits are most highly upregulated during maturation-stage amelogenesis: a time when ameloblast endocytotic activity is highest. Western blot analyses, using specific antibodies to four of the V-type ATPase subunits (Atp6v0d2, Atp6v1b2, Atp6v1c1 and Atp6v1e1), were then applied to validate much of the qPCR data. Immunohistochemistry using these same four antibodies was also performed to identify the spatiotemporal expression profiles of individual V-type ATPase subunits. Our data show that cytoplasmic V-type ATPase is significantly upregulated in enamel organ cells during maturation-stage when compared to secretory-stage. These data likely relate to the higher endocytotic activities, and the greater need for lysosomal acidification, during maturation-stage amelogenesis. It is also apparent from our immunolocalization data, using antibodies against two of the V-type ATPase subunits (Atp6v1c1 and Atp6v1e1), that significant expression is seen at the apical membrane of maturation-stage ameloblasts. Others have also identified this V-type ATPase expression profile at the apical membrane of maturation ameloblasts. Collectively, these data better define the expression and role of the V-type ATPase proton pump in the enamel organ during amelogenesis.
Topics: Ameloblasts; Animals; Cytoplasm; Dental Enamel; Enamel Organ; Endosomes; Gene Expression Regulation, Developmental; Lysosomes; Male; Rats; Vacuolar Proton-Translocating ATPases
PubMed: 26586472
DOI: 10.1016/j.matbio.2015.11.004