title: Alteration of conserved alternative splicing in AMELX causes enamel defects.
abstract: Tooth enamel is the most highly mineralized tissue in vertebrates. Enamel crystal formation and elongation should be well controlled to achieve an exceptional hardness and a compact microstructure. Enamel matrix calcification occurs with several matrix proteins, such as amelogenin, enamelin, and ameloblastin. Among them, amelogenin is the most abundant enamel matrix protein, and multiple isoforms resulting from extensive but well-conserved alternative splicing and postsecretional processing have been identified. In this report, we recruited a family with a unique enamel defect and identified a silent mutation in exon 4 of the AMELX gene. We show that the mutation caused the inclusion of exon 4, which is almost always skipped, in the mRNA transcript. We further show, by generating and characterizing a transgenic animal model, that the alteration of the ratio and quantity of the developmentally conserved alternative splicing repertoire of AMELX caused defects in enamel matrix mineralization.
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Chonbuk National University, Jeonju, Korea.
authors.forename: E S
authors.initials: ES
authors.lastname: Cho
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: K-J
authors.initials: KJ
authors.lastname: Kim
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: K-E
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Cluster for Craniofacial Development and Regeneration Research, Institute of Oral Biosciences, School of Dentistry, Chonbuk National University, Jeonju, Korea.
authors.forename: C Y
authors.initials: CY
authors.lastname: Yun
authors.affiliation: Division in Anatomy and Developmental Biology, Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Korea.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Lee
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: T J
authors.initials: TJ
authors.lastname: Shin
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: H-K
authors.initials: HK
authors.lastname: Hyun
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: Y-J
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: S-H
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division in Anatomy and Developmental Biology, Department of Oral Biology, College of Dentistry, Yonsei University, Seoul, Korea.
authors.forename: H-S
authors.initials: HS
authors.lastname: Jung
authors.affiliation: Department of Cell and Developmental Biology and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: Z H
authors.initials: ZH
authors.lastname: Lee
authors.affiliation: Department of Pediatric Dentistry and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea Department of Molecular Genetics and Dental Research Institute, School of Dentistry, Seoul National University, Seoul, Korea pedoman@snu.ac.kr.
authors.forename: J-W
authors.initials: JW
authors.lastname: Kim
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000565:Ameloblasts / Q000473:pathology; D000567:Amelogenesis Imperfecta / Q000235:genetics* / Q000473:pathology; D053523:Amelogenin / Q000235:genetics*; D000818:Animals; D002648:Child; D017124:Conserved Sequence / Q000235:genetics*; D003461:Crystallography; D003743:Dental Enamel / Q000473:pathology / Q000648:ultrastructure; D005091:Exons / Q000235:genetics; D005260:Female; D008040:Genetic Linkage; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018895:Microsatellite Repeats / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C507199:AMELX protein, human; D053523:Amelogenin; C507200:Amelx protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger
keywords: X-linked; amelogenesis imperfecta; amelogenin; mRNA splicing; silent mutation; tooth