Birgitta Bäckman

A deletion in the amelogenin gene (AMG) causes X-linked amelogenesis imperfecta (AIH1)

Amelogenesis imperfecta is characterized by the defective formation of tooth enamel. Here we present evidence that the X-linked form of this disorder (AIH1) is caused by a structural alteration in one of the predominant proteins in enamel, amelogenin. Southern blot analysis revealed a deletion extending over 5 kb of the amelogenin gene in males with the hypomineralization form of the AIH1. Carrier females were heterozygous for the molecular defect. The deletion appears to include at least two exons of the amelogenin gene and the extent of the deletion was verified by PCR analysis. The mutation was shown to segregate with the disease among 15 analyzed individuals belonging to the same kindred. Our results link a defect in the amelogenin gene to the abnormal formation of enamel. We thus conclude that the amelogenin protein has a role in biomineralization of tooth enamel.

Amelogenin signal peptide mutation: correlation between mutations in the amelogenin gene (AMGX) and manifestations of X-linked amelogenesis imperfecta.

Formation of tooth enamel is a poorly understood biological process. In this study we describe a 9-bp deletion in exon 2 of the amelogenin gene (AMGX) causing X-linked hypoplastic amelogenesis imperfecta, a disease characterized by defective enamel. The mutation results in the loss of 3 amino acids and exchange of 1 in the signal peptide of the amelogenin protein. This deletion in the signal peptide probably interferes with translocation of the amelogenin protein during synthesis, resulting in the thin enamel observed in affected members of the family. We compare this mutation to a previously reported mutation in the amelogenin gene that causes a different disease phenotype. The study illustrates that molecular analysis can help explain the various manifestations of a tooth disorder and thereby provide insights into the mechanisms of tooth enamel formation.

GENETIC HETEROGENEITY OF AUTOSOMAL DOMINANT AMELOGENESIS IMPERFECTA DEMONSTRATED BY ITS EXCLUSION FROM THE AIH2 REGION ON HUMAN CHROMOSOME 4Q

Amelogenesis imperfecta (AI) is a group of hereditary enamel defects, characterized by large clinical diversity. On the basis of differences in clinical manifestation and inheritance pattern, 14 different subtypes have been recognized. A locus for autosomal dominant AI (ADAI) of local hypoplastic type was recently mapped to the region between D4S392 and D4S395 on the long arm of chromosome 4. To test whether the chromosome 4 locus is responsible for other forms of AI as well, a linkage study was carried out with 17 families representing at least five clinical forms of ADAI. Admixture tests for heterogeneity performed with the marker D4S2456 gave statistical support for genetic heterogeneity of ADAI with the odds 78:1. Linkage to the ADAI locus on chromosome 4q (AIH2) could only be demonstrated with families expressing the local hypoplastic type, and there was no support for heterogeneity within that group of families. Furthermore, linkage could be excluded for five families with other clinical forms of ADAI. The data therefore demonstrated that ADAI is genetically heterogeneous, and that at least two loci for it exist.

Enamel defects in extracted and exfoliated teeth from patients with Amelogenesis Imperfecta, measured using the extended enamel defects index and image analysis

Aims To enhance the phenotypic description and quantification of enamel defects from a North Sweden sample of extracted and exfoliated teeth originating from families with Amelogenesis Imperfecta by use of the extended enamel defects index (EDI) and image analysis to demonstrate the comparable reliability and value of the additional measurements. Methods and results The sample comprised 109 deciduous and 7 permanent teeth from 32 individuals of 19 families with Amelogenesis Imperfecta in Northern Sweden. A special holder for individual teeth was designed and the whole sample was examined using the extended EDI and an image analysis system. In addition to the extended EDI definitions, the calibrated images were measured for tooth surface area, defect area and percentage of surface affected using image analysis techniques. The extended EDI was assessed using weighted and unweighted Kappa statistics. The reliability of imaging and measurement was determined using Fleiss’ intra-class correlation coefficient (ICCC). Kappa values indicated good or excellent intra-operator repeatability and inter-operator reproducibility for the extended EDI. The Fleiss ICCC values indicated excellent repeatability for the image analysis measurements. Hypoplastic pits on the occlusal surfaces were the most frequent defect in this sample (82.6%). The occlusal surface displayed the most post-eruptive breakdown (39.13%) whilst the incisal portion of the buccal surfaces showed most diffuse opacities (53.4%). Image analysis methods demonstrated the largest mean hypoplastic pit areas were on the lingual surfaces. The largest mean post-eruptive breakdown areas were on the lingual surfaces of posterior teeth. The largest mean demarcated opacity areas were found on the labial surfaces. Conclusions The extended EDI and the standardised image acquisition and analysis system provided additional information to conventional measurement techniques. Additional phenotypic variables were described.

Exclusion of p63 as a candidate gene for autosomal-dominant amelogenesis imperfecta

Objective. Mutations within the p63 gene have been shown to cause ectodermal dysplasia syndromes affecting a spectrum of developmental abnormalities, including ectodermal appendages, e.g. enamel. The affected teeth have a similar phenotype as another dental disorder, amelogenesis imperfecta (AI), a disease of genetically determined abnormal enamel formation in the absence of systemic symptoms. The genetic basis of particular forms of AI has been found, although the gene(s) responsible for the most prevalent AI types has not been identified. Material and Methods. DNA samples of 41 individuals (25 affected and 16 unaffected) from 6 Swedish families with autosomal-dominant AI were screened for mutations (by partially denaturing HPLC) and sequenced. Results. No mutation in p63 was found in these families. Conclusions. p63 is not responsible for different forms of autosomal-dominant AI in the Swedish families studied. The roles of p63 in tooth development and in the genetic etiology of AI remain to be identified.