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Journal of Dental Research May 2015
Review
Topics: Amelogenesis; Amino Acid Sequence; Animals; Conserved Sequence; Dental Enamel; Dental Enamel Proteins; Gene Duplication; Humans; Mice; Mice, Transgenic
PubMed: 25900605
DOI: 10.1177/0022034515572442 -
Scientific Reports Feb 2022As the hardest tissue in the human body, tooth enamel formation is a highly regulated process involving several stages of differentiation and key regulatory genes. One...
As the hardest tissue in the human body, tooth enamel formation is a highly regulated process involving several stages of differentiation and key regulatory genes. One such gene, tryptophan-aspartate repeat domain 72 (WDR72), has been found to cause a tooth enamel defect when deleted or mutated, resulting in a condition called amelogenesis imperfecta. Unlike the canonical genes regulating tooth development, WDR72 remains intracellularly and is not secreted to the enamel matrix space to regulate mineralization, and is found in other major organs of the body, namely the kidney, brain, liver, and heart. To date, a link between intracellular vesicle transport and enamel mineralization has been suggested, however identification of the mechanistic regulators has yet to be elucidated, in part due to the limitations associated with studying highly differentiated ameloblast cells. Here we show compelling evidence that WDR72 regulates endocytosis of proteins, both in vivo and in a novel in vitro ameloblast cell line. We elucidate WDR72's function to be independent of intracellular vesicle acidification while still leading to defective enamel matrix pH extracellularly. We identify a vesicle function associated with microtubule assembly and propose that WDR72 directs microtubule assembly necessary for membrane mobilization and subsequent vesicle transport. Understanding WDR72 function provides a mechanistic basis for determining physiologic and pathologic tissue mineralization.
Topics: Ameloblasts; Amelogenesis Imperfecta; Brain; Calcification, Physiologic; Cell Differentiation; Dental Enamel; Endocytosis; Humans; Kidney; Liver; Microtubules; Myocardium; Tooth
PubMed: 35181734
DOI: 10.1038/s41598-022-06751-1 -
Journal of Personalized Medicine Feb 2023Amelogenesis imperfecta (AI) is a heterogeneous collection of hereditary enamel defects. The affected enamel can be classified as hypoplastic, hypomaturation, or...
Amelogenesis imperfecta (AI) is a heterogeneous collection of hereditary enamel defects. The affected enamel can be classified as hypoplastic, hypomaturation, or hypocalcified in form. A better understanding of normal amelogenesis and improvements in our ability to diagnose AI through genetic testing can be realized through more complete knowledge of the genes and disease-causing variants that cause AI. In this study, mutational analysis was performed with whole exome sequencing (WES) to identify genetic etiology underlying the hypomaturation AI condition in affected families. Mutational analyses identified biallelic mutations in four hypomaturation AI families. Novel mutations include a homozygous deletion and insertion mutation (NM_182758.4: c.2680_2699delinsACTATAGTT, p.(Ser894Thrfs*15)), compound heterozygous mutations (paternal c.2332dupA, p.(Met778Asnfs*4)) and (maternal c.1287_1289del, p.(Ile430del)) and a homozygous 3694 bp deletion that includes exon 14 (NG_017034.2:g.96472_100165del). A homozygous recurrent mutation variant (c.1467_1468delAT, p.(Val491Aspfs*8)) was also identified. Current ideas on WDR72 structure and function are discussed. These cases expand the mutational spectrum of mutations causing hypomaturation AI and improve the possibility of genetic testing to accurately diagnose AI caused by defects.
PubMed: 36836560
DOI: 10.3390/jpm13020326 -
Frontiers in Physiology 2020Stromal interaction molecule 1 () is one of the main components of the store operated Ca entry (SOCE) signaling pathway. Individuals with mutated present severely...
BACKGROUND
Stromal interaction molecule 1 () is one of the main components of the store operated Ca entry (SOCE) signaling pathway. Individuals with mutated present severely hypomineralized enamel characterized as amelogenesis imperfecta (AI) but the downstream molecular mechanisms involved remain unclear. Circadian clock signaling plays a key role in regulating the enamel thickness and mineralization, but the effects of -mediated AI on circadian clock are unknown.
OBJECTIVES
The aim of this study is to examine the potential links between SOCE and the circadian clock during amelogenesis.
METHODS
We have generated mice with ameloblast-specific deletion of ( /Amelx-iCre, cKO) and analyzed circadian gene expression profile in compared to control ( /Amelx-iCre) using ameloblast micro-dissection and RNA micro-array of 84 circadian genes. Expression level changes were validated by qRT-PCR and immunohistochemistry.
RESULTS
deletion has resulted in significant upregulation of the core circadian activator gene Brain and Muscle Aryl Hydrocarbon Receptor Nuclear Translocation 1 () and downregulation of the circadian inhibitor Period 2 (). Our analyses also revealed that SOCE disruption results in dysregulation of two additional circadian regulators; p38α mitogen-activated protein kinase (MAPK14) and transforming growth factor-beta1 (TGF-β1). Both MAPK14 and TGF-β1 pathways are known to play major roles in enamel secretion and their dysregulation has been previously implicated in the development of AI phenotype.
CONCLUSION
These data indicate that disruption of SOCE significantly affects the ameloblasts molecular circadian clock, suggesting that alteration of the circadian clock may be partly involved in the development of -mediated AI.
PubMed: 32848861
DOI: 10.3389/fphys.2020.00920 -
Head & Face Medicine Jun 2024Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can...
INTRODUCTION
Amelogenesis imperfecta (AI) is a genetically determined, non-syndromic enamel dysplasia that may manifest as hypoplasia, hypomaturation, or hypocalcification and can commonly be classified into four primary groups. In this retrospective analysis, specific orofacial characteristics are described and associated with each of the AI types based on a patient cohort from Witten/Herdecke University, Germany.
METHODS
Data from 19 patients (ten male and nine female, mean age 12.27 ± 4.06 years) with AI who presented at the Department of Orthodontics between July 2011 and December 2023 were analyzed. Baseline skeletal and dental conditions were assessed, including the presence of hypodontia, displacements, and taurodontism. AI was classified into classes I-IV based on phenotype. Treatment needs were evaluated according to the main findings following the German KIG classification, while the radiological enamel situation was determined using panoramic radiographs.
RESULTS
An approximately equal distribution between classes II and III was found and a slight inclination toward a dolichofacial configuration (ΔML-NSL: 5.07 ± 9.23°, ΔML-NL: 4.24 ± 8.04°). Regarding orthodontic findings, disturbance in tooth eruption as well as open bite were the most prevalent issues (both 36.8%, n = 7). The most common AI classes were type I and II, which show an almost even distribution about the skeletal classes in sagittal dimension, while dolichofacial configuration was found most frequently in vertical dimension.
CONCLUSION
Both clinical and radiological orthodontic findings in context with AI are subject to extensive distribution. It seems that no specific orofacial findings can be confirmed in association with AI with regard to the common simple classes I-IV. It may be more appropriate to differentiate the many subtypes according to their genetic aspects to identify possible associated orthodontic findings.
Topics: Humans; Amelogenesis Imperfecta; Male; Female; Retrospective Studies; Child; Adolescent; Germany; Radiography, Panoramic; Orthodontics, Corrective; Malocclusion
PubMed: 38877506
DOI: 10.1186/s13005-024-00436-y -
Frontiers in Physiology 2017During the secretory phase of their life-cycle, ameloblasts are highly specialized secretory cells whose role is to elaborate an extracellular matrix that ultimately... (Review)
Review
During the secretory phase of their life-cycle, ameloblasts are highly specialized secretory cells whose role is to elaborate an extracellular matrix that ultimately confers both form and function to dental enamel, the most highly mineralized of all mammalian tissues. In common with many other "professional" secretory cells, ameloblasts employ the unfolded protein response (UPR) to help them cope with the large secretory cargo of extracellular matrix proteins transiting their ER (endoplasmic reticulum)/Golgi complex and so minimize ER stress. However, the UPR is a double-edged sword, and, in cases where ER stress is severe and prolonged, the UPR switches from pro-survival to pro-apoptotic mode. The purpose of this review is to consider the role of the ameloblast UPR in the biology and pathology of amelogenesis; specifically in respect of amelogenesis imperfecta (AI) and fluorosis. Some forms of AI appear to correspond to classic proteopathies, where pathological intra-cellular accumulations of protein tip the UPR toward apoptosis. Fluorosis also involves the UPR and, while not of itself a classic proteopathic disease, shares some common elements through the involvement of the UPR. The possibility of therapeutic intervention by pharmacological modulation of the UPR in AI and fluorosis is also discussed.
PubMed: 28951722
DOI: 10.3389/fphys.2017.00653 -
International Journal of Paediatric... Nov 2022Amelogenesis imperfecta (AI) is an inherited disorder of enamel development that is challenging to treat and often associated with negative patient and parental...
BACKGROUND
Amelogenesis imperfecta (AI) is an inherited disorder of enamel development that is challenging to treat and often associated with negative patient and parental outcomes. Social media provides a valuable perspective on patients' and dental professionals' experience of AI and dental care.
AIM
To explore how the public and dental professionals use social media to discuss AI.
DESIGN
A cross-sectional study involving a systemic search of eight social media platforms using the search term 'amelogenesis imperfecta'. Relevant posts were selected using predefined eligibility criteria. Word content of eligible posts was qualitatively analysed using a thematic framework approach.
RESULTS
A total of 555 posts were identified, of which 144 were eligible for analysis. For dental professionals, the posts included case reports and seeking and sharing of information. For the public, the posts were related to individuals' experience of AI, dental treatment and outcome of treatment.
CONCLUSIONS
Posts from individuals affected by AI suggest a need for better distribution of reliable information and greater support. Case reports indicate that dental professionals find it challenging to recognise AI and determine appropriate treatment options. Social media could potentially be used to inform and support people with AI and allow dental professionals to share information and learning with peers.
Topics: Amelogenesis; Amelogenesis Imperfecta; Cross-Sectional Studies; Dentists; Humans; Social Media
PubMed: 35771161
DOI: 10.1111/ipd.13015 -
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 -
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 -
Advances in Clinical and Experimental... Dec 2022Taurodontism is a morphological anomaly involving multirooted teeth that is characterized by a vertical shift of the pulp chamber and shortening of the roots. The... (Review)
Review
Taurodontism is a morphological anomaly involving multirooted teeth that is characterized by a vertical shift of the pulp chamber and shortening of the roots. The literature was analyzed to determine the impact of a diagnosis of taurodontism on dental treatment. A total of 85 full-text publications from the years 2005-2021 were analyzed and 20 publications were included in this research. The endodontic treatment of a taurodont tooth is challenging due to the apical displacement of the pulpal chamber floor and the incorrect configuration of the root canal system, or the presence of additional canals. In terms of prosthetics, the use of taurodont teeth as abutments is not recommended as they lack stability due to shorter roots. The extraction of taurodont teeth can be complicated due to an apical shift of the root furcation. In periodontology, taurodont teeth can have a better prognosis as there is less chance of furcation involvement. From an orthodontic point of view, it is important to note that taurodont teeth are not sufficiently embedded in the alveolus and have a greater tendency for root resorption. With regard to genetic diseases, it has been reported that this anomaly can exist as an isolated feature. However, the majority of authors agree that taurodontism is associated with conditions such as Down syndrome, Klinefelter syndrome, cleft lip and palate, hypodontia, amelogenesis imperfecta, and others. From a clinical standpoint, it is very important to diagnose taurodontism before treatment. A diagnosis of taurodontism can be important in the early diagnosis of malformations that commonly occur with this condition.
Topics: Humans; Dental Pulp Cavity; Cleft Lip; Cleft Palate; Tooth Abnormalities
PubMed: 36000881
DOI: 10.17219/acem/152120