title: Deletion of amelotin exons 3-6 is associated with amelogenesis imperfecta.
abstract: 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.
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.|Department of Oral Biology, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Claire E L
authors.initials: CE
authors.lastname: Smith
authors.affiliation: University of Costa Rica, School of Dentistry, San Pedro, Costa Rica.
authors.forename: Gina
authors.initials: G
authors.lastname: Murillo
authors.affiliation: Department of Oral Biology, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Brookes
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: James A
authors.initials: JA
authors.lastname: Poulter
authors.affiliation: University of Costa Rica, Molecular Biology Cellular Centre (CBCM), San Pedro, Costa Rica and.
authors.forename: Sandra
authors.initials: S
authors.lastname: Silva
authors.affiliation: Department of Oral Biology, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kirkham
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Chris F
authors.initials: CF
authors.lastname: Inglehearn
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK, a.j.mighell@leeds.ac.uk.|School of Dentistry, University of Leeds, Leeds LS2 9LU, UK.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mighell
mesh_terms: D000567:Amelogenesis Imperfecta / Q000235:genetics* / Q000503:physiopathology; D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D003743:Dental Enamel / Q000254:growth & development / Q000473:pathology*; D003746:Dental Enamel Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C507066:Amtn protein, mouse; D003746:Dental Enamel Proteins