Amelogenesis imperfecta (AI) represents hereditary conditions affecting the quality and quantity of enamel. Six genes are known to cause AI (AMELX, ENAM, MMP20, KLK4, FAM83H, and WDR72). Our aim was to determine the distribution of different gene mutations in a large AI population and evaluate phenotype-genotype relationships. Affected and unaffected family members were evaluated clinically and radiographically by one examiner. Genotyping was completed using genomic DNA obtained from blood or saliva. A total of 494 individuals were enrolled, with 430 (224 affected, 202 unaffected, and 4 not definitive) belonging to 71 families with conditions consistent with the diagnosis of AI. Diverse clinical phenotypes were observed (i.e. hypoplastic, hypocalcified, and hypomaturation). Genotyping revealed mutations in all 6 candidate genes. A molecular diagnosis was made in 132 affected individuals (59%) and in 26 of the families (37%). Mutations involved 12 families with FAM83H (46%), 6 families with AMELX (23%), 3 families with ENAM (11%), 2 families with KLK4 and MMP20 (8% for each gene), and 1 family with a WDR72 mutation (4%). Phenotypic variants were associated with allelic FAM83H and AMELX mutations. Two seemingly unrelated families had the same KLK4 mutation. Families affected with AI where candidate gene mutations were not identified could have mutations not identifiable by traditional gene sequencing (e.g. exon deletion) or they could have promoter sequence mutations not evaluated in this study. However, the results suggest that there remain new AI causative genes to be identified.
Congenitally missing teeth (tooth agenesis) represents the most common craniofacial anomaly in man, affecting up to 20% of the population worldwide. Tooth agenesis is a clinically heterogeneous disorder affecting specific tooth types at different rates. Recent evidence also confirms the role of genetic heterogeneity in this common dental anomaly, with two genes, MSX1 and PAX9, contributing to the majority of cases published. Previous studies have associated mutations in PAX9 with molar oligodontia, while others have associated mutations in MSX1 primarily with premolar hypodontia. Most of these studies have focused on individuals who are otherwise normal and affected with this disorder.ObjectiveOur objective was therefore to determine if alterations in MSX1 and PAX9 might also be responsible for tooth agenesis in families also affected with dental syndromes including tricho dento osseous syndrome (TDO) or amelogenesis imperfecta (AI).MethodsTo test whether mutations in MSX1 and PAX9 are responsible for cases of tooth agenesis occurring with specific dental anomalies, we used direct sequencing of PCR products. Clinical examination, pedigree analysis, followed by PCR-based mutational analysis of MSX1 was carried out for affected individuals and unaffected relatives.ResultsPedigree analysis revealed that tooth agenesis was transmitted as an autosomal dominant trait in all families examined. Direct sequencing of the coding region revealed the presence of non-synonymous SNPs in MSX1 and PAX9 for affected and unaffected family members.ConclusionOur results support the conclusion that tooth agenesis is due to genetic heterogeneity and suggest that MSX1 may cooperate with PAX9 in the patterning of human dentition, and also that a unique haplotype may be present in families segregating tooth agenesis and either TDO or AI. Supported by the AAOF (S.F.-B.) and NIH grant 1K23RR17442-01 (S.F.-B.).
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