Spectrum of pathogenic variants and founder effects in amelogenesis imperfecta associated with MMP20.

Amelogenesis imperfecta (AI) describes a heterogeneous group of developmental enamel defects that typically have Mendelian inheritance. Exome sequencing of 10 families with recessive hypomaturation AI revealed four novel and one known variants in the matrix metallopeptidase 20 (MMP20) gene that were predicted to be pathogenic. MMP20 encodes a protease that cleaves the developing extracellular enamel matrix and is necessary for normal enamel crystal growth during amelogenesis. New homozygous missense changes were shared between four families of Pakistani heritage (c.625G>C; p.(Glu209Gln)) and two of Omani origin (c.710C>A; p.(Ser237Tyr)). In two families of UK origin and one from Costa Rica, affected individuals were homozygous for the previously reported c.954-2A>T; p.(Ile319Phefs*19) variant. For each of these variants, microsatellite haplotypes appeared to exclude a recent founder effect, but elements of haplotype were conserved, suggesting more distant founding ancestors. New compound heterozygous changes were identified in one family of the European heritage: c.809_811+12delinsCCAG; p.(?) and c.1122A>C; p.(Gln374His). This report further elucidates the mutation spectrum of MMP20 and the probable impact on protein function, confirms a consistent hypomaturation phenotype and shows that mutations in MMP20 are a common cause of autosomal recessive AI in some communities.

New missense variants in RELT causing hypomineralised amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic diseases characterised by dental enamel malformation. Pathogenic variants in at least 33 genes cause syndromic or non-syndromic AI. Recently variants in RELT, encoding an orphan receptor in the tumour necrosis factor (TNF) superfamily, were found to cause recessive AI, as part of a syndrome encompassing small stature and severe childhood infections. Here we describe four additional families with autosomal recessive hypomineralised AI due to previously unreported homozygous mutations in RELT. Three families carried a homozygous missense variant in the fourth exon (c.164C>T, p.(T55I)) and a fourth family carried a homozygous missense variant in the 11th exon (c.1264C>T, p.(R422W)). We found no evidence of additional syndromic symptoms in affected individuals. Analyses of tooth microstructure with computerised tomography and scanning electron microscopy suggest a role for RELT in ameloblasts' coordination and interaction with the enamel matrix. Microsatellite genotyping in families segregating the T55I variant reveals a shared founder haplotype. These findings extend the RELT pathogenic variant spectrum, reveal a founder mutation in the UK Pakistani population and provide detailed analysis of human teeth affected by this hypomineralised phenotype, but do not support a possible syndromic presentation in all those with RELT-variant associated AI.

Prevalence and Severity of Plaque-Induced Gingivitis in Three Latin American Cities: Mexico City-Mexico, Great Metropolitan Area-Costa Rica and Bogota-Colombia / Prevalencia y severidad de gingivitis inducida por placa en tres ciudades de Latinoamérica: Ciudad de México-México, Gran Área Metropolitana-Costa Rica y Bogotá- Colombia

Abstract Plaque-induced gingivitis is the most common form of periodontal disease and can affect 100% of the population. Gingivitis prevalence in Latin American population is not well documented, therefore the aim of this study was to determine the prevalence and severity of plaque-induced gingivitis in adult populations of three Latin American cities. Methods: This cross sectional multicenter study included 1650 participants, 550 from the Great Metropolitan Area of Costa Rica (GAM), 550 from Mexico City, Mexico (CDMX) and 550 from Bogota City, Colombia (BC). Subjects completed a questionnaire about their medical history and oral hygiene. Clinical assessment included recording of missing teeth, visible plaque index, calculus recording and gingival index (GI, Loe-Silness index). Results: Average GI was 1.36. No statistical difference was found between GAM (1.45) and BC (1.48); however, GI in CDMX was significantly lower (1.16). Average gingival bleeding on probing was 43%. Total plaque index was 0.76 showing the highest accumulation at interproximal sites (p=0.0001). A positive correlation was found between plaque and gingivitis (r=0.59). Dental calculus was present in at least one of the 18 evaluated sites per subject with no statistical difference between cities. There was no statistical difference in GI between smokers, former smokers and non- smokers. Conclusion: Gingivitis prevalence was 99.6%. Moderate Gingivitis was the predominant form, with no statistically significant difference between cities or gender. Dental plaque accumulation was the most important risk factor associated with the establishment of the disease.

Resumen La gingivitis inducida por placa es la forma más común de enfermedad periodontal y puede afectar al 100% de la población. La prevalencia de gingivitis en Latinoamerica no está bien documentada, por lo tanto, el objetivo de este estudio fue determinar la prevalencia y severidad de la gingivitis inducida por placa en poblaciones adultas de tres ciudades latinamericanas. Metodología: Este estudio transversal multicéntrico incluyó 1650 sujetos, 550 del Gran Área Metropolitana de Costa Rica (GAM), 550 de la Ciudad de México, México (CDMX) y 550 de la Ciudad de Bogotá, Colombia (BC). Los sujetos completaron un cuestionario sobre su historia médica y hábitos de higiene oral. El examen clínico incluyó el registro de piezas dentales ausentes, el índice de placa visible, el registro de cálculo y el índice gingival (GI, Índice de Silness y Loe). Resultados: El GI promedio fue de 1.36. No se encontró diferencia estadísticamente significativa entre GAM (1.45) y BC (1.48); sin embargo, el índice gingival en CDMX fue menor (1.16). El promedio de sangrado al sondaje fue de 43%. El índice de placa total fue 0.76, mostrando la mayor acumulación en sitios interproximales (p=0.0001). Se encontró una correlación positiva entre placa y gingivitis (r=0.59). Hubo presencia de cálculo dental en al menos uno de los 18 sitios evaluados por cada sujeto sin diferencia estadística entre ciudades. No se encontró diferencia estadísticamente significativa en cuanto al índice gingival entre fumadores, ex fumadores y no fumadores. Conclusión: La prevalencia de Gingivitis fue del 99.6%. La Gingivitis Moderada fue la forma predominante, sin diferencia estadísticamente significativa por ciudad o sexo. La acumulación de placa fue el principal factor de riesgo asociado con el establecimiento de la enfermedad.

Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. Amelotin (AMTN) is a secreted protein thought to act as a promoter of matrix mineralization in the final stage of enamel development, and is strongly expressed, almost exclusively, in maturation stage ameloblasts. Amtn overexpression and Amtn knockout mouse models have defective enamel with no other associated phenotypes, highlighting AMTN as an excellent candidate gene for human AI. However, no AMTN mutations have yet been associated with human AI. Using whole exome sequencing, we identified an 8,678 bp heterozygous genomic deletion encompassing exons 3-6 of AMTN in a Costa Rican family segregating dominant hypomineralised AI. The deletion corresponds to an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 residues. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects at least some of which appeared to be associated with organic material as evidenced using elemental analysis. This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function.

Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.

Amelogenesis imperfecta (AI) describes a heterogeneous group of inherited dental enamel defects reflecting failure of normal amelogenesis. Ameloblastin (AMBN) is the second most abundant enamel matrix protein expressed during amelogenesis. The pivotal role of AMBN in amelogenesis has been confirmed experimentally using mouse models. However, no AMBN mutations have been associated with human AI. Using autozygosity mapping and exome sequencing, we identified genomic deletion of AMBN exon 6 in a second cousin consanguineous family with three of the six children having hypoplastic AI. The genomic deletion corresponds to an in-frame deletion of 79 amino acids, shortening the protein from 447 to 368 residues. Exfoliated primary teeth (unmatched to genotype) were available from family members. The most severely affected had thin, aprismatic enamel (similar to that reported in mice homozygous for Ambn lacking exons 5 and 6). Other teeth exhibited thicker but largely aprismatic enamel. One tooth had apparently normal enamel. It has been suggested that AMBN may function in bone development. No clinically obvious bone or other co-segregating health problems were identified in the family investigated. This study confirms for the first time that AMBN mutations cause non-syndromic human AI and that mouse models with disrupted Ambn function are valid.