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1.
Genes (Basel) ; 13(5)2022 05 12.
Article in English | MEDLINE | ID: mdl-35627243

ABSTRACT

Mutations in Dentin Sialophosphoprotein (DSPP) are known to cause, in order of increasing severity, dentin dysplasia type-II (DD-II), dentinogenesis imperfecta type-II (DGI-II), and dentinogenesis imperfecta type-III (DGI-III). DSPP mutations fall into two groups: a 5'-group that affects protein targeting and a 3'-group that shifts translation into the −1 reading frame. Using whole-exome sequence (WES) analyses and Single Molecule Real-Time (SMRT) sequencing, we identified disease-causing DSPP mutations in 12 families. Three of the mutations are novel: c.53T>C/p.(Val18Ala); c.3461delG/p.(Ser1154Metfs*160); and c.3700delA/p.(Ser1234Alafs*80). We propose genetic analysis start with WES analysis of proband DNA to identify mutations in COL1A1 and COL1A2 causing dominant forms of osteogenesis imperfecta, 5'-DSPP mutations, and 3'-DSPP frameshifts near the margins of the DSPP repeat region, and SMRT sequencing when the disease-causing mutation is not identified. After reviewing the literature and incorporating new information showing distinct differences in the cell pathology observed between knockin mice with 5'-Dspp or 3'-Dspp mutations, we propose a modified Shields Classification based upon the causative mutation rather than phenotypic severity such that patients identified with 5'-DSPP defects be diagnosed as DGI-III, while those with 3'-DSPP defects be diagnosed as DGI-II.


Subject(s)
Dentinogenesis Imperfecta , Animals , Dentinogenesis Imperfecta/genetics , Extracellular Matrix Proteins/genetics , Humans , Mice , Mutation , Pedigree , Phosphoproteins/genetics , Sialoglycoproteins/genetics
2.
J Clin Pediatr Dent ; 46(1): 6-11, 2022 Jan 01.
Article in English | MEDLINE | ID: mdl-35311983

ABSTRACT

OBJECTIVE: To investigate the staining outcomes of Silver Diamine Fluoride (SDF) after its application on healthy enamel and its implications on patient's caries risk assessment. STUDY DESIGN: A review of dental and photographic records of 61 caries-free subjects under age 3, who received SDF application as part of a prevention protocol in a private pediatric dental clinic was performed. The age, gender, caries risk assessment and resulting staining were analyzed. RESULTS: Three groups of staining outcomes after SDF application were found: Group 1: no staining (32.8%). Group 2: removable staining (31.1%). Group 3: permanent staining (36.1%). The patterns of the staining were similar to initial lesion distributions in Early Childhood Caries (ECC). The deft scores for all subjects were zero before treatment and remained so at the end of this study except one subject from Group 3 who showed clinical signs of caries at follow-up visits. CONCLUSIONS: There are three possible staining outcomes following SDF application on clinically healthy enamel for children under age three without previous caries history; no staining, removable staining and permanent staining. The patterns of the staining were similar to initial lesion distributions in ECC. SDF application may be of use in identifying previously undetected young children with high caries risk. Further research is needed to elucidate the mechanism and cause of staining and to examine the association of the staining outcomes with the future caries incidence of the subject.


Subject(s)
Cariostatic Agents , Dental Caries Susceptibility , Cariostatic Agents/therapeutic use , Child , Child, Preschool , Fluorides, Topical/therapeutic use , Humans , Quaternary Ammonium Compounds , Silver Compounds , Staining and Labeling
3.
PLoS One ; 7(12): e51533, 2012.
Article in English | MEDLINE | ID: mdl-23227268

ABSTRACT

Inherited dentin defects are classified into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia (DD). The genetic etiology of DD-I is unknown. Defects in dentin sialophosphoprotein (DSPP) cause DD type II and DGI types II and III. DGI type I is the oral manifestation of osteogenesis imperfecta (OI), a systemic disease typically caused by defects in COL1A1 or COL1A2. Mutations in MSX1, PAX9, AXIN2, EDA and WNT10A can cause non-syndromic familial tooth agenesis. In this study a simplex pattern of clinical dentinogenesis imperfecta juxtaposed with a dominant pattern of hypodontia (mild tooth agenesis) was evaluated, and available family members were recruited. Mutational analyses of the candidate genes for DGI and hypodontia were performed and the results validated. A spontaneous novel mutation in COL1A2 (c.1171G>A; p.Gly391Ser) causing only dentin defects and a novel mutation in PAX9 (c.43T>A; p.Phe15Ile) causing hypodontia were identified and correlated with the phenotypic presentations in the family. Bone radiographs of the proband's dominant leg and foot were within normal limits. We conclude that when no DSPP mutation is identified in clinically determined isolated DGI cases, COL1A1 and COL1A2 should be considered as candidate genes. PAX9 mutation p.Phe15Ile within the N-terminal ß-hairpin structure of the PAX9 paired domain causes tooth agenesis.


Subject(s)
Bone and Bones/abnormalities , Collagen Type I/genetics , Dentinogenesis Imperfecta/genetics , Mutation, Missense/genetics , Osteogenesis Imperfecta/genetics , PAX9 Transcription Factor/genetics , Tooth Abnormalities/genetics , Base Sequence , Bone and Bones/diagnostic imaging , Child, Preschool , Dentinogenesis Imperfecta/diagnostic imaging , Female , Genetic Predisposition to Disease , Humans , Male , Molecular Sequence Data , Osteogenesis Imperfecta/diagnostic imaging , Pedigree , Radiography , Tooth/diagnostic imaging , Tooth Abnormalities/diagnostic imaging
4.
PLoS One ; 7(12): e52052, 2012.
Article in English | MEDLINE | ID: mdl-23251683

ABSTRACT

Amelogenesis imperfecta (AI) is a group of inherited conditions featuring isolated enamel malformations. About 5% of AI cases show an X-linked pattern of inheritance, which are caused by mutations in AMELX. In humans there are two, non-allelic amelogenin genes: AMELX (Xp22.3) and AMELY (Yp11.2). About 90% of amelogenin expression is from AMELX, which is nested within intron 1 of the gene encoding Rho GTPase activating protein 6 (ARHGAP6). We recruited two AI families and determined that their disease-causing mutations were partial deletions in ARHGAP6 that completely deleted AMELX. Affected males in both families had a distinctive enamel phenotype resembling "snow-capped" teeth. The 96,240 bp deletion in family 1 was confined to intron 1 of ARHGAP6 (g.302534_398773del96240), but removed alternative ARHGAP6 promoters 1c and 1d. Analyses of developing teeth in mice showed that ARHGAP6 is not expressed from these promoters in ameloblasts. The 52,654 bp deletion in family 2 (g.363924_416577del52654insA) removed ARHGAP6 promoter 1d and exon 2, precluding normal expression of ARHGAP6. The male proband of family 2 had slightly thinner enamel with greater surface roughness, but exhibited the same pattern of enamel malformations characteristic of males in family 1, which themselves showed minor variations in their enamel phenotypes. We conclude that the enamel defects in both families were caused by amelogenin insufficiency, that deletion of AMELX results in males with a characteristic snow-capped enamel phenotype, and failed ARHGAP6 expression did not appreciably alter the severity of enamel defects when AMELX was absent.


Subject(s)
Amelogenesis Imperfecta/genetics , Amelogenin/genetics , GTPase-Activating Proteins/genetics , Sequence Deletion , Adolescent , Animals , Child , Child, Preschool , Dental Enamel/pathology , Dental Enamel Proteins/genetics , Exons/genetics , Genetic Predisposition to Disease , Humans , Introns , Male , Mice , Phenotype , Promoter Regions, Genetic , Tooth/pathology
5.
Eur J Oral Sci ; 119 Suppl 1: 158-67, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22243242

ABSTRACT

Dentin sialophosphoprotein (DSPP) mutations cause dentin dysplasia type II (DD-II) and dentinogenesis imperfecta types II and III (DGI-II and DGI-III, respectively). We identified two kindreds with DGI-II who exhibited vertical bands of hypoplastic enamel. Both families had a previously reported DSPP mutation that segregated with the disease phenotype. Oral photographs and dental radiographs of four affected and one unaffected participant in one family and of the proband in the second family were used to document the dental phenotypes. We aligned the 33 unique allelic DSPP sequences showing variable patterns of insertions and deletions (indels), generated a merged dentin phosphoprotein (DPP) sequence that includes sequences from all DSPP length haplotypes, and mapped the known DSPP mutations in this context. Analyses of the DSPP sequence changes and their probable effects on protein expression, as well as published findings of the dental phenotype in Dspp null mice, support the hypothesis that all DSPP mutations cause pathology through dominant-negative effects. Noting that Dspp is transiently expressed by mouse pre-ameloblasts during formation of the dentino-enamel junction, we hypothesize that DSPP dominant-negative effects potentially cause cellular pathology in pre-ameloblasts that, in turn, causes enamel defects. We conclude that enamel defects can be part of the dental phenotype caused by DSPP mutations, although DSPP is not critical for dental enamel formation.


Subject(s)
Dental Enamel Hypoplasia/genetics , Dentin Dysplasia/genetics , Dentinogenesis Imperfecta/genetics , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/physiology , Phosphoproteins/genetics , Phosphoproteins/physiology , Sialoglycoproteins/genetics , Sialoglycoproteins/physiology , Adolescent , Ameloblasts/metabolism , Ameloblasts/pathology , Amino Acid Sequence , DNA Mutational Analysis , Female , Genes, Dominant , Genotype , Haplotypes , Humans , Male , Molecular Sequence Data , Mutation , Pedigree , Phenotype
6.
Eur J Oral Sci ; 119 Suppl 1: 311-23, 2011 Dec.
Article in English | MEDLINE | ID: mdl-22243262

ABSTRACT

Previously, mutational analyses identified six disease-causing mutations in 24 amelogenesis imperfecta (AI) kindreds. We have since expanded the number of AI kindreds to 39, and performed mutation analyses covering the coding exons and adjoining intron sequences for the six proven AI candidate genes [amelogenin (AMELX), enamelin (ENAM), family with sequence similarity 83, member H (FAM83H), WD repeat containing domain 72 (WDR72), enamelysin (MMP20), and kallikrein-related peptidase 4 (KLK4)] and for ameloblastin (AMBN) (a suspected candidate gene). All four of the X-linked AI families (100%) had disease-causing mutations in AMELX, suggesting that AMELX is the only gene involved in the aetiology of X-linked AI. Eighteen families showed an autosomal-dominant pattern of inheritance. Disease-causing mutations were identified in 12 (67%): eight in FAM83H, and four in ENAM. No FAM83H coding-region or splice-junction mutations were identified in three probands with autosomal-dominant hypocalcification AI (ADHCAI), suggesting that a second gene may contribute to the aetiology of ADHCAI. Six families showed an autosomal-recessive pattern of inheritance, and disease-causing mutations were identified in three (50%): two in MMP20, and one in WDR72. No disease-causing mutations were found in 11 families with only one affected member. We conclude that mutation analyses of the current candidate genes for AI have about a 50% chance of identifying the disease-causing mutation in a given kindred.


Subject(s)
Amelogenesis Imperfecta/genetics , Dental Enamel Proteins/genetics , Amelogenin/genetics , Child , Child, Preschool , Chromosomes, Human, X/genetics , DNA Mutational Analysis , Female , Genes, Dominant , Genes, Recessive , Humans , Inheritance Patterns/genetics , Kallikreins/genetics , Male , Matrix Metalloproteinase 20/genetics , Mutation , Pedigree , Proteins/genetics
7.
J Periodontol ; 81(7): 982-91, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20384462

ABSTRACT

BACKGROUND: Infection is a risk factor for preterm birth. This study was conducted in the field and addressed the link between periodontal pathogens measured with the benzoyl-DL-arginine-naphthylamide (BANA) test and preterm birth. METHODS: This prospective study was performed in Changhua, Taiwan. Periodontal examinations included the plaque index, papillary bleeding scores, and measurement of the BANA enzyme in plaque samples at the second and third trimesters. Independent variables included maternal demographic characteristics, previous pregnancy histories, risk factors, plaque and gingivitis scores, and current pregnancy outcomes. RESULTS: There were 19 (7%) preterm deliveries among the 268 subjects. A history of a previous preterm birth and low birth weight, frequency of prenatal visits, preterm uterine contractions, antepartum hemorrhages, placenta previae, and preterm premature rupture of membranes were significantly related to preterm birth (P = 0.035, 0.027, <0.001, 0.025, 0.006, 0.014, and <0.001, respectively). Maternal weight gain was higher with a normal term delivery (P = 0.003). Multivariable logistic regression analyses showed that the number of BANA-infected sites in the third trimester (odds ratio [OR]: 5.89; 95% confidence interval [CI]: 1.5 to 31.6), maternal weight gain (OR: 0.78; 95% CI: 0.65 to 0.91), antepartum hemorrhages (OR: 10.0; 95% CI: 2.2 to 46.9), and preterm premature rupture of membranes (OR: 12.6; 95% CI: 3.97 to 42.71) had significant influences on preterm-birth outcomes. CONCLUSIONS: BANA-positive plaque in the third trimester was associated with preterm births after controlling for other risk factors. The BANA test can be used to screen pregnant women at chairside and/or bedside to apply suitable intervention tactics.


Subject(s)
Benzoylarginine-2-Naphthylamide/analysis , Periodontal Diseases/classification , Premature Birth/etiology , Adolescent , Adult , Dental Plaque/enzymology , Dental Plaque Index , Female , Fetal Membranes, Premature Rupture , Gingival Hemorrhage/classification , Gingivitis/classification , Humans , Infant, Low Birth Weight , Infant, Newborn , Obstetric Labor, Premature , Periodontal Diseases/enzymology , Periodontal Index , Placenta Previa , Pregnancy , Pregnancy Outcome , Pregnancy Trimester, Second , Pregnancy Trimester, Third , Prenatal Care , Prospective Studies , Risk Factors , Uterine Contraction/physiology , Uterine Hemorrhage/complications , Young Adult
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