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1.
Head Face Med ; 20(1): 36, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38877506

ABSTRACT

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.


Subject(s)
Amelogenesis Imperfecta , Humans , Amelogenesis Imperfecta/therapy , Amelogenesis Imperfecta/genetics , Male , Female , Retrospective Studies , Child , Adolescent , Germany , Radiography, Panoramic , Orthodontics, Corrective/methods , Malocclusion/therapy
2.
J Dent ; 147: 105149, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38909645

ABSTRACT

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 and 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.


Subject(s)
Amelogenesis Imperfecta , Quality of Life , Humans , Amelogenesis Imperfecta/therapy , Amelogenesis Imperfecta/diagnosis , Adolescent , Child , Crowns , Dental Restoration, Permanent/methods , Esthetics, Dental , Composite Resins , Genetic Testing
3.
Int J Mol Sci ; 25(11)2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38892321

ABSTRACT

AMELX mutations cause X-linked amelogenesis imperfecta (AI), known as AI types IE, IIB, and IIC in Witkop's classification, characterized by hypoplastic (reduced thickness) and/or hypomaturation (reduced hardness) enamel defects. In this study, we conducted whole exome analyses to unravel the disease-causing mutations for six AI families. Splicing assays, immunoblotting, and quantitative RT-PCR were conducted to investigate the molecular and cellular effects of the mutations. Four AMELX pathogenic variants (NM_182680.1:c.2T>C; c.29T>C; c.77del; c.145-1G>A) and a whole gene deletion (NG_012494.2:g.307534_403773del) were identified. The affected individuals exhibited enamel malformations, ranging from thin, poorly mineralized enamel with a "snow-capped" appearance to severe hypoplastic defects with minimal enamel. The c.145-1G>A mutation caused a -1 frameshift (NP_001133.1:p.Val35Cysfs*5). Overexpression of c.2T>C and c.29T>C AMELX demonstrated that mutant amelogenin proteins failed to be secreted, causing elevated endoplasmic reticulum stress and potential cell apoptosis. This study reveals a genotype-phenotype relationship for AMELX-associated AI: While amorphic mutations, including large deletions and 5' truncations, of AMELX cause hypoplastic-hypomaturation enamel with snow-capped teeth (AI types IIB and IIC) due to a complete loss of gene function, neomorphic variants, including signal peptide defects and 3' truncations, lead to severe hypoplastic/aplastic enamel (AI type IE) probably caused by "toxic" cellular effects of the mutant proteins.


Subject(s)
Amelogenesis Imperfecta , Amelogenin , Genetic Association Studies , Mutation , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/pathology , Humans , Amelogenin/genetics , Male , Female , Pedigree , Phenotype , Child , Endoplasmic Reticulum Stress/genetics , Genotype , Exome Sequencing
4.
Arch Oral Biol ; 164: 105991, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38761453

ABSTRACT

OBJECTIVES: To identify the genetic cause of a Chinese family with hypomaturation amelogenesis imperfecta (AI) and to characterize the structure of GPR68 mutated enamel in order to develop a deeper understanding of the role of the GPR68 protein during the intricate process of amelogenesis. DESIGN: One Chinese family with generalized hypomaturation AI was recruited. Two of the third molars from the proband were subjected to scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDX). Whole exome sequencing (WES) was performed, and the identified mutation was confirmed by Sanger sequencing. Bioinformatics studies were further conducted to analyze the potential deleterious effects of the mutation. RESULTS: The proband presented with a hypomaturation AI phenotype, characterized by fragile and discolored enamel surface. The AI enamel showed prismatic structure, which was sporadically obscured by areas of amorphous material and porous structure. EDX analysis showed the proband's enamel demonstrated a significant decrease in calcium and phosphorus content and a significant increase in oxygen compared with normal enamel. A novel homozygous mutation of G protein-coupled receptor 68 (GPR68) (c .149 T > A, p.Ile50Asn) was identified in the proband. Bioinformatics analysis indicated that the mutation site displayed a high level of evolutionary conservation among species, and the mutation might impact the stability and conformation of the protein. CONCLUSION: The novel homozygous GPR68 mutation resulted in hypomaturation AI. We first described the effect of GPR68 mutation on enamel structure. Our results provide new genetic evidence that mutations involved in GPR68 contribute to hypomaturation AI.


Subject(s)
Amelogenesis Imperfecta , Dental Enamel , Exome Sequencing , Microscopy, Electron, Scanning , Mutation , Receptors, G-Protein-Coupled , Female , Humans , Male , Amelogenesis Imperfecta/genetics , China , Computational Biology/methods , Pedigree , Phenotype , Receptors, G-Protein-Coupled/genetics , Spectrometry, X-Ray Emission
5.
J Dent Res ; 103(6): 662-671, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38716742

ABSTRACT

Amelogenesis imperfecta (AI) is a diverse group of inherited diseases featured by various presentations of enamel malformations that are caused by disturbances at different stages of enamel formation. While hypoplastic AI suggests a thickness defect of enamel resulting from aberrations during the secretory stage of amelogenesis, hypomaturation AI indicates a deficiency of enamel mineralization and hardness established at the maturation stage. Mutations in ENAM, which encodes the largest enamel matrix protein, enamelin, have been demonstrated to cause generalized or local hypoplastic AI. Here, we characterized 2 AI families with disparate hypoplastic and hypomaturation enamel defects and identified 2 distinct indel mutations at the same location of ENAM, c588+1del and c.588+1dup. Minigene splicing assays demonstrated that they caused frameshifts and truncation of ENAM proteins, p.Asn197Ilefs*81 and p.Asn197Glufs*25, respectively. In situ hybridization of Enam on mouse mandibular incisors confirmed its restricted expression in secretory stage ameloblasts and suggested an indirect pathogenic mechanism underlying hypomaturation AI. In silico analyses indicated that these 2 truncated ENAMs might form amyloid structures and cause protein aggregation with themselves and with wild-type protein through the added aberrant region at their C-termini. Consistently, protein secretion assays demonstrated that the truncated proteins cannot be properly secreted and impede secretion of wild-type ENAM. Moreover, compared to the wild-type, overexpression of the mutant proteins significantly increased endoplasmic reticulum stress and upregulated the expression of unfolded protein response (UPR)-related genes and TNFRSF10B, a UPR-controlled proapoptotic gene. Caspase, terminal deoxynucleotidyl transferase UTP nick-end labeling (TUNEL), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays further revealed that both truncated proteins, especially p.Asn197Ilefs*81, induced cell apoptosis and decreased cell survival, suggesting that the 2 ENAM mutations cause AI through ameloblast cell pathology and death rather than through a simple loss of function. This study demonstrates that an ENAM mutation can lead to generalized hypomaturation enamel defects and suggests proteinopathy as a potential pathogenesis for ENAM-associated AI.


Subject(s)
Amelogenesis Imperfecta , Amelogenesis Imperfecta/genetics , Animals , Mice , Humans , Ameloblasts/pathology , Female , Male , Mutation , Dental Enamel Proteins/genetics , Pedigree , Apoptosis/genetics , In Situ Hybridization , Extracellular Matrix Proteins
6.
Matrix Biol ; 131: 62-76, 2024 Aug.
Article in English | MEDLINE | ID: mdl-38815936

ABSTRACT

Extracellular matrix proteins play crucial roles in the formation of mineralized tissues like bone and teeth via multifunctional mechanisms. In tooth enamel, ameloblastin (Ambn) is one such multifunctional extracellular matrix protein implicated in cell signaling and polarity, cell adhesion to the developing enamel matrix, and stabilization of prismatic enamel morphology. To provide a perspective for Ambn structure and function, we begin this review by describing dental enamel and enamel formation (amelogenesis) followed by a description of enamel extracellular matrix. We then summarize the established domains and motifs in Ambn protein, human amelogenesis imperfecta cases, and genetically engineered mouse models involving mutated or null Ambn. We subsequently delineate in silico, in vitro, and in vivo evidence for the amphipathic helix in Ambn as a proposed cell-matrix adhesive and then more recent in vitro evidence for the multitargeting domain as the basis for dynamic interactions of Ambn with itself, amelogenin, and membranes. The multitargeting domain facilitates tuning between Ambn-membrane interactions and self/co-assembly and supports a likely overall role for Ambn as a matricellular protein. We anticipate that this review will enhance the understanding of multifunctional matrix proteins by consolidating diverse mechanisms through which Ambn contributes to enamel extracellular matrix mineralization.


Subject(s)
Amelogenesis Imperfecta , Amelogenesis , Dental Enamel Proteins , Dental Enamel , Extracellular Matrix , Humans , Animals , Dental Enamel Proteins/metabolism , Dental Enamel Proteins/genetics , Amelogenesis/genetics , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/metabolism , Amelogenesis Imperfecta/pathology , Mice , Dental Enamel/metabolism , Dental Enamel/chemistry , Extracellular Matrix/metabolism , Amelogenin/metabolism , Amelogenin/genetics , Amelogenin/chemistry , Cell Adhesion
7.
Swiss Dent J ; 134(1): 84-104, 2024 Feb 19.
Article in German | MEDLINE | ID: mdl-38739045

ABSTRACT

The aim of the treatment of this case was to restore the form, function and aesthetics of all teeth in a patient with amelogenesis imperfecta within the age limit of the disability insurance (IV). Single-tooth zirconia crowns were selected as the treatment of choice and cemented with a conventional glass ionomer cement. For the maintenance of the oral rehabilitation and the protection of the reconstructions a michigan splint was produced and instructed to be carried over night.


Subject(s)
Amelogenesis Imperfecta , Crowns , Humans , Amelogenesis Imperfecta/rehabilitation , Glass Ionomer Cements/therapeutic use , Zirconium , Female , Male , Esthetics, Dental , Dental Prosthesis Design , Occlusal Splints
8.
J Dent Child (Chic) ; 91(1): 38-42, 2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38671566

ABSTRACT

Enamel renal gingival syndrome is a rare clinical condition characterized by the presence of amelogenesis imperfecta hypoplastic type, gingival fibromatosis and delayed tooth eruption, in addition to nephrocalcinosis with normal blood calcium levels. It is inherited as an autosomal recessive trait caused by mutations in the FAM20A gene located on chromosome 17q24.2. The purpose of this report is to describe a case of enamel renal gingival syndrome and discuss its distinct features and management.


Subject(s)
Amelogenesis Imperfecta , Nephrocalcinosis , Humans , Male , Amelogenesis Imperfecta/complications , Amelogenesis Imperfecta/genetics , Dental Enamel Proteins/genetics , Dental Enamel Proteins/therapeutic use , Fibromatosis, Gingival/genetics , Fibromatosis, Gingival/complications , Child
10.
Sci Rep ; 14(1): 9497, 2024 04 25.
Article in English | MEDLINE | ID: mdl-38664418

ABSTRACT

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.


Subject(s)
Abnormalities, Multiple , Adaptor Proteins, Signal Transducing , Cleft Palate , Dental Enamel Hypoplasia , Exophthalmos , Fibroblasts , Fibrosis , Gingiva , Osteosclerosis , Proteomics , Signal Transduction , Transcription Factors , Transforming Growth Factor beta , YAP-Signaling Proteins , Humans , Transforming Growth Factor beta/metabolism , Gingiva/metabolism , Gingiva/pathology , Proteomics/methods , Fibrosis/metabolism , YAP-Signaling Proteins/metabolism , YAP-Signaling Proteins/genetics , Osteosclerosis/metabolism , Osteosclerosis/genetics , Osteosclerosis/pathology , Adaptor Proteins, Signal Transducing/metabolism , Adaptor Proteins, Signal Transducing/genetics , Transcription Factors/metabolism , Transcription Factors/genetics , Dental Enamel Hypoplasia/metabolism , Dental Enamel Hypoplasia/genetics , Dental Enamel Hypoplasia/pathology , Fibroblasts/metabolism , Fibroblasts/pathology , Microcephaly/metabolism , Microcephaly/genetics , Microcephaly/pathology , Female , Transcriptional Coactivator with PDZ-Binding Motif Proteins/metabolism , Male , Trans-Activators/metabolism , Trans-Activators/genetics , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Casein Kinase I/metabolism , Casein Kinase I/genetics , Extracellular Matrix Proteins/metabolism , Extracellular Matrix Proteins/genetics , Amelogenesis Imperfecta/metabolism , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/pathology , Cells, Cultured
11.
JAMA Dermatol ; 160(5): 544-549, 2024 May 01.
Article in English | MEDLINE | ID: mdl-38506824

ABSTRACT

Importance: Kindler epidermolysis bullosa is a genetic skin-blistering disease associated with recessive inherited pathogenic variants in FERMT1, which encodes kindlin-1. Severe orofacial manifestations of Kindler epidermolysis bullosa, including early oral squamous cell carcinoma, have been reported. Objective: To determine whether hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa. Design, Settings, and Participants: This longitudinal, 2-center cohort study was performed from 2003 to 2023 at the Epidermolysis Bullosa Centre, University of Freiburg, Germany, and the Special Care Dentistry Clinic, University of Chile in association with DEBRA Chile. Participants included a convenience sampling of all patients with a diagnosis of Kindler epidermolysis bullosa. Main Outcomes and Measures: The primary outcomes were the presence of hypoplastic pitted amelogenesis imperfecta, intraoral wounds, gingivitis and periodontal disease, gingival hyperplasia, vestibular obliteration, cheilitis, angular cheilitis, chronic lip wounds, microstomia, and oral squamous cell carcinoma. Results: The cohort consisted of 36 patients (15 female [42%] and 21 male [58%]; mean age at first examination, 23 years [range, 2 weeks to 70 years]) with Kindler epidermolysis bullosa. The follow-up ranged from 1 to 24 years. The enamel structure was assessed in 11 patients, all of whom presented with enamel structure abnormalities. The severity of hypoplastic pitted amelogenesis imperfecta varied from generalized to localized pitting. Additional orofacial features observed include gingivitis and periodontal disease, which was present in 90% (27 of 30 patients) of those assessed, followed by intraoral lesions (16 of 22 patients [73%]), angular cheilitis (24 of 33 patients [73%]), cheilitis (22 of 34 patients [65%]), gingival overgrowth (17 of 26 patients [65%]), microstomia (14 of 25 patients [56%]), and vestibular obliteration (8 of 16 patients [50%]). Other features included chronic lip ulcers (2 patients) and oral squamous cell carcinoma with lethal outcome (2 patients). Conclusions and Relevance: These findings suggest that hypoplastic pitted amelogenesis imperfecta is a feature of Kindler epidermolysis bullosa and underscore the extent and severity of oral manifestations in Kindler epidermolysis bullosa and the need for early and sustained dental care.


Subject(s)
Epidermolysis Bullosa , Humans , Male , Female , Adult , Young Adult , Child, Preschool , Adolescent , Child , Epidermolysis Bullosa/complications , Middle Aged , Longitudinal Studies , Periodontal Diseases/complications , Periodontal Diseases/epidemiology , Carcinoma, Squamous Cell/pathology , Amelogenesis Imperfecta/complications , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/pathology , Cohort Studies , Mouth Neoplasms/pathology , Mouth Neoplasms/complications , Gingivitis/pathology , Gingivitis/etiology , Cheilitis , Chile
12.
J Med Genet ; 61(7): 689-698, 2024 Jun 20.
Article in English | MEDLINE | ID: mdl-38458752

ABSTRACT

BACKGROUND: Plexins are large transmembrane receptors for the semaphorin family of signalling proteins. Semaphorin-plexin signalling controls cellular interactions that are critical during development as well as in adult life stages. Nine plexin genes have been identified in humans, but despite the apparent importance of plexins in development, only biallelic PLXND1 and PLXNA1 variants have so far been associated with Mendelian genetic disease. METHODS: Eight individuals from six families presented with a recessively inherited variable clinical condition, with core features of amelogenesis imperfecta (AI) and sensorineural hearing loss (SNHL), with variable intellectual disability. Probands were investigated by exome or genome sequencing. Common variants and those unlikely to affect function were excluded. Variants consistent with autosomal recessive inheritance were prioritised. Variant segregation analysis was performed by Sanger sequencing. RNA expression analysis was conducted in C57Bl6 mice. RESULTS: Rare biallelic pathogenic variants in plexin B2 (PLXNB2), a large transmembrane semaphorin receptor protein, were found to segregate with disease in all six families. The variants identified include missense, nonsense, splicing changes and a multiexon deletion. Plxnb2 expression was detected in differentiating ameloblasts. CONCLUSION: We identify rare biallelic pathogenic variants in PLXNB2 as a cause of a new autosomal recessive, phenotypically diverse syndrome with AI and SNHL as core features. Intellectual disability, ocular disease, ear developmental abnormalities and lymphoedema were also present in multiple cases. The variable syndromic human phenotype overlaps with that seen in Plxnb2 knockout mice, and, together with the rarity of human PLXNB2 variants, may explain why pathogenic variants in PLXNB2 have not been reported previously.


Subject(s)
Amelogenesis Imperfecta , Intellectual Disability , Pedigree , Humans , Animals , Male , Female , Mice , Intellectual Disability/genetics , Intellectual Disability/pathology , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/pathology , Receptors, Cell Surface/genetics , Nerve Tissue Proteins/genetics , Alleles , Child , Hearing Loss/genetics , Hearing Loss/pathology , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/pathology , Adult , Mutation/genetics , Adolescent , Child, Preschool , Phenotype
13.
Int Endod J ; 57(6): 745-758, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38477421

ABSTRACT

AIM: Loss-of-function mutations in FAM20A result in amelogenesis imperfecta IG (AI1G) or enamel-renal syndrome, characterized by hypoplastic enamel, ectopic calcification, and gingival hyperplasia, with some cases reporting spontaneous tooth infection. Despite previous reports on the consequence of FAM20A reduction in gingival fibroblasts and transcriptome analyses of AI1G pulp tissues, suggesting its involvement in mineralization and infection, its role in deciduous dental pulp cells (DDP) remains unreported. The aim of this study was to evaluate the properties of DDP obtained from an AI1G patient, providing additional insights into the effects of FAM20A on the mineralization of DDP. METHODOLOGY: DDP were obtained from a FAM20A-AI1G patient (mutant cells) and three healthy individuals. Cellular behaviours were examined using flow cytometry, MTT, attachment and spreading, colony formation, and wound healing assays. Osteogenic induction was applied to DDP, followed by alizarin red S staining to assess their osteogenic differentiation. The expression of FAM20A-related genes, osteogenic genes, and inflammatory genes was analysed using real-time PCR, Western blot, and/or immunolocalization. Additionally, STRING analysis was performed to predict potential protein-protein interaction networks. RESULTS: The mutant cells exhibited a significant reduction in FAM20A mRNA and protein levels, as well as proliferation, migration, attachment, and colony formation. However, normal FAM20A subcellular localization was maintained. Additionally, osteogenic/odontogenic genes, OSX, OPN, RUNX2, BSP, and DSPP, were downregulated, along with upregulated ALP. STRING analysis suggested a potential correlation between FAM20A and these osteogenic genes. After osteogenic induction, the mutant cells demonstrated reduced mineral deposition and dysregulated expression of osteogenic genes. Remarkably, FAM20A, FAM20C, RUNX2, OPN, and OSX were significantly upregulated in the mutant cells, whilst ALP, and OCN was downregulated. Furthermore, the mutant cells exhibited a significant increase in inflammatory gene expression, that is, IL-1ß and TGF-ß1, whereas IL-6 and NFκB1 expression was significantly reduced. CONCLUSION: The reduction of FAM20A in mutant DDP is associated with various cellular deficiencies, including delayed proliferation, attachment, spreading, and migration as well as altered osteogenic and inflammatory responses. These findings provide novel insights into the biology of FAM20A in dental pulp cells and shed light on the molecular mechanisms underlying AI1G pathology.


Subject(s)
Amelogenesis Imperfecta , Cell Differentiation , Dental Enamel Proteins , Dental Pulp , Nephrocalcinosis , Osteogenesis , Tooth, Deciduous , Humans , Cells, Cultured , Dental Enamel Proteins/genetics , Dental Enamel Proteins/metabolism , Dental Pulp/cytology , Dental Pulp/metabolism , Gene Expression , Mutation , Osteogenesis/genetics
14.
Chin J Dent Res ; 27(1): 53-63, 2024 Mar 28.
Article in English | MEDLINE | ID: mdl-38546520

ABSTRACT

OBJECTIVE: To investigate FAM20A gene variants and histological features of amelogenesis imperfecta and to further explore the functional impact of these variants. METHODS: Whole-exome sequencing (WES) and Sanger sequencing were used to identify pathogenic gene variants in three Chinese families with amelogenesis imperfecta. Bioinformatics analysis, in vitro histological examinations and experiments were conducted to study the functional impact of gene variants, and the histological features of enamel, keratinised oral mucosa and dental follicle. RESULTS: The authors identified two nonsense variants c. 406C > T (p.Arg136*) and c.826C > T (p.Arg176*) in a compound heterozygous state in family 1, two novel frameshift variants c.936dupC (p.Val313Argfs*67) and c.1483dupC (p.Leu495Profs*44) in a compound heterozygous state in family 2, and a novel homozygous frameshift variant c.530_531insGGTC (p.Ser178Valfs*21) in family 3. The enamel structure was abnormal, and psammomatoid calcifications were identified in both the gingival mucosa and dental follicle. The bioinformatics and subcellular localisation analyses indicated these variants to be pathogenic. The secondary and tertiary structure analysis speculated that these five variants would cause structural damage to FAM20A protein. CONCLUSION: The present results broaden the variant spectrum and clinical and histological findings of diseases associated with FAM20A, and provide useful information for future genetic counselling and functional investigation.


Subject(s)
Amelogenesis Imperfecta , Dental Enamel Proteins , Humans , Amelogenesis Imperfecta/genetics , Calcification, Physiologic , Computational Biology , Dental Enamel , Dental Enamel Proteins/genetics , East Asian People
15.
Eur J Ophthalmol ; 34(4): NP1-NP5, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38488462

ABSTRACT

INTRODUCTION: Heimler syndrome (HS) is a rare disorder that includes sensorineural hearing loss (SNHL), nail abnormalities, and enamel hypoplasia. Patients with this syndrome can also exhibit ocular manifestations. At present, only a few cases of HS have been reported, existing knowledge of this syndrome is limited, and many cases have been misdiagnosed or even missed. This is the first report of Heimler syndrome with blurred vision as the first complaint, which was diagnosed by genetic analysis in the ophthalmology department. CASE DESCRIPTION: An 8-year-old girl complained of bilateral visual blur and night blindness from birth. Ophthalmic examinations revealed bilateral retinitis pigmentosa with cystoid macular edema, visual impairment with hyperopia and astigmatism. Hearing test revealed bilateral severe sensorineural hearing loss. Dental examinations revealed enamel hypoplasia. In addition, whole-exome sequencing (WES) identified two pathogenic variants in PEX1: the previously reported missense variant c.2966T > C (p.I989 T), and the novel frameshift variant c.1671_1672del (p.G558Sfs*33). CONCLUSION: Heimler syndrome is caused by compound heterozygous PEX1 pathogenic variants, c.2966T > C (p.I989 T) and c.1671_1672del (p.G558Sfs*33), which contributed to the diversity of clinical and genetic profiles in this patient. The main clinical manifestations include bilateral retinitis pigmentosa with cystoid macular edema, sensorineural hearing loss, and enamel hypoplasia. Systemic examinations are suggested for patients suspected of having pigmentary retinal dystrophy, especially combined with hearing-related impairments. Genetic testing can help us to make a definitive diagnosis.


Subject(s)
Amelogenesis Imperfecta , Hearing Loss, Sensorineural , Nails, Malformed , Humans , Female , Child , Hearing Loss, Sensorineural/genetics , Hearing Loss, Sensorineural/diagnosis , Nails, Malformed/genetics , Nails, Malformed/diagnosis , Amelogenesis Imperfecta/genetics , Amelogenesis Imperfecta/diagnosis , Visual Acuity , Heterozygote , DNA Mutational Analysis , Exome Sequencing , Tomography, Optical Coherence , Vision Disorders/genetics , Vision Disorders/diagnosis , Membrane Proteins/genetics , DNA/genetics , ATPases Associated with Diverse Cellular Activities
17.
FASEB J ; 38(4): e23497, 2024 Feb 29.
Article in English | MEDLINE | ID: mdl-38376916

ABSTRACT

This study investigated the possible roles of renal estrogen receptors (ER) in glomerulonephritis associated with small vessel vasculitis. The relationships of ERs were investigated in antineutrophilic cytoplasmic antibody (ANCA)-associated glomerulonephritis and immunoglobulin A (IgA) nephropathy groups, which are small vessel vasculitis subtypes with two different glomerulonephritis development pathophysiologies. The design of this study was prepared as a retrospective cohort study. The study included 42 patients with ANCA-associated vasculitis and 18 with IgA nephropathy in the small vessel vasculitis group. For the control group, intact renal tissues of 28 patients who underwent nephrectomy due to renal cell carcinoma were used. Renal biopsy samples of the groups were stained with ER beta (ß) and ER alpha (α). Tubular ER ß expression score (TERßES) median values were found to be significantly higher in ANCA- associated vasculitis (B = 0.724, OR [95%CI]: 2.064 [1.141-3.731], p = .016) and IgA nephropathy (B = 0.898, OR [95%CI]: 2.454 [1.307-4.609], p = .005) than in intact kidney tissue. It was determined that tubular ERß was most frequently localized in the distal tubule at 57.9% and the second most common in the proximal tubule at 20.4%. The expression of tubular ERß is increased in glomerulonephritis due to small vessel vasculitis. Tubular ERßs are most commonly localized in the distal tubule. Further studies are needed to understand the physiological and pathophysiological effects of altered renal ER levels in small vessel vasculitis.


Subject(s)
Amelogenesis Imperfecta , Glomerulonephritis, IGA , Glomerulonephritis , Kidney Neoplasms , Nephrocalcinosis , Vasculitis , Humans , Receptors, Estrogen , Antibodies, Antineutrophil Cytoplasmic , Retrospective Studies , Kidney , Estrogens
18.
Eur Arch Paediatr Dent ; 25(1): 85-91, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38308725

ABSTRACT

BACKGROUND: Amelogenesis imperfecta (AI) and dentinogenesis imperfecta (DI) are two groups of genetically inherited conditions resulting in abnormal enamel and dentin formation, respectively. Children and young people may be adversely affected by these conditions, with significant reduction in oral health related quality of life. Dental management of children with AI and DI is often complex, which is exacerbated by the absence of clear referral pathways and scarce evidence-based guidelines. METHOD: The need for increased knowledge and peer support led to the development of a group of UK paediatric dentists with a special clinical interest in the management of children with AI and DI. PURPOSE: The aims of this paper are to describe the establishment of an AI/DI Clinical Excellence Network (AI/DI CEN) in paediatric dentistry including outputs and future plans, and to share our collective learning to help support others anywhere in the world advance the care of people with AI or DI.


Subject(s)
Amelogenesis Imperfecta , Dentinogenesis Imperfecta , Child , Humans , Adolescent , Amelogenesis Imperfecta/therapy , Dentinogenesis Imperfecta/therapy , Quality of Life , Dentin , United Kingdom
19.
J Esthet Restor Dent ; 36(6): 881-891, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38258433

ABSTRACT

OBJECTIVE: The aim of this review was to compare various types of restorations used in children and young adults affected with amelogenesis imperfecta (AI) to determine the most effective restorative treatment. METHODS: This systematic review included randomized controlled trials, retrospective and prospective cohorts conducted on children and young adults diagnosed with amelogenesis imperfecta and written in French or English. A systematic search was conducted using four databases, namely Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE via PubMed, Science Direct and Scopus, using a selection of MeSH terms: "Amelogenesis Imperfecta," "Therapeutics," "Treatment Outcome," "Adult, young," "Child," "Dental Restoration, Permanent," "Dental Restoration, Temporary," and "Esthetics, Dental." RESULTS: Out of 138 articles identified in the initial search, four articles met all the inclusion criteria. The results showed that ceramic restorations had better quality scores and longevity compared to other restorations. CONCLUSION: Ceramic restorations could be considered the restorative treatment modality of choice for AI-affected children and young adults. However, more high-quality clinical trials involving young patients affected with AI are required to evaluate and compare the outcomes of different restorative approaches. CLINICAL SIGNIFICANCE: Young patients affected with amelogenesis imperfecta usually suffer from low self-esteem, psychological problems and social avoidance, caused by the alteration of teeth such as discoloration, sensitivity, fractures and reduced size. For the dentist, selecting the appropriate restorative treatment for AI in young patients could be a veritable challenge. Therefore, it is important to have an evidence-based modality. For this reason, in this review, the different restorative approaches used in AI-affected young patients were compared to recommend the most effective treatment.


Subject(s)
Amelogenesis Imperfecta , Humans , Amelogenesis Imperfecta/therapy , Child , Dental Restoration, Permanent/methods , Young Adult , Adolescent
20.
Sci Rep ; 14(1): 445, 2024 01 03.
Article in English | MEDLINE | ID: mdl-38172607

ABSTRACT

Kohlschütter-Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by severe intellectual disability, early-onset epileptic seizures, and amelogenesis imperfecta. Here, we present a novel Rogdi mutant mouse deleting exons 6-11- a mutation found in KTS patients disabling ROGDI function. This Rogdi-/- mutant model recapitulates most KTS symptoms. Mutants displayed pentylenetetrazol-induced seizures, confirming epilepsy susceptibility. Spontaneous locomotion and circadian activity tests demonstrate Rogdi mutant hyperactivity mirroring patient spasticity. Object recognition impairment indicates memory deficits. Rogdi-/- mutant enamel was markedly less mature. Scanning electron microscopy confirmed its hypomineralized/hypomature crystallization, as well as its low mineral content. Transcriptomic RNA sequencing of postnatal day 5 lower incisors showed downregulated enamel matrix proteins Enam, Amelx, and Ambn. Enamel crystallization appears highly pH-dependent, cycling between an acidic and neutral pH during enamel maturation. Rogdi-/- teeth exhibit no signs of cyclic dental acidification. Additionally, expression changes in Wdr72, Slc9a3r2, and Atp6v0c were identified as potential contributors to these tooth acidification abnormalities. These proteins interact through the acidifying V-ATPase complex. Here, we present the Rogdi-/- mutant as a novel model to partially decipher KTS pathophysiology. Rogdi-/- mutant defects in acidification might explain the unusual combination of enamel and rare neurological disease symptoms.


Subject(s)
Amelogenesis Imperfecta , Dementia , Epilepsy , Tooth Abnormalities , Humans , Animals , Mice , Amelogenesis Imperfecta/genetics , Seizures , Mutation , Membrane Proteins/genetics , Nuclear Proteins/genetics
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