title: Deletion of ameloblastin exon 6 is associated with amelogenesis imperfecta.
abstract: 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.
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: School of Dentistry and.
authors.forename: Gina
authors.initials: G
authors.lastname: Murillo
authors.affiliation: School of Dentistry, University of Leeds, Leeds LS2 9LU, 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: Claire E L
authors.initials: CE
authors.lastname: Smith
authors.affiliation: Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: Biology, Molecular Cellular Centre (CBCM), University of Costa Rica, San Pedro, Costa Rica.
authors.forename: Sandra
authors.initials: S
authors.lastname: Silva
authors.affiliation: School of Dentistry, University of Leeds, Leeds LS2 9LU, 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 School of Dentistry, University of Leeds, Leeds LS2 9LU, UK a.j.mighell@leeds.ac.uk.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Mighell
mesh_terms: D000567:Amelogenesis Imperfecta / Q000235:genetics / Q000473:pathology*; D000595:Amino Acid Sequence; D000818:Animals; D003746:Dental Enamel Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014070:Tooth / Q000473:pathology / Q000648:ultrastructure*
chemical_list: C490889:AMBN protein, human; D003746:Dental Enamel Proteins