title: Novel human mutation and CRISPR/Cas genome-edited mice reveal the importance of C-terminal domain of MSX1 in tooth and palate development.
abstract: Several mutations, located mainly in the MSX1 homeodomain, have been identified in non-syndromic tooth agenesis predominantly affecting premolars and third molars. We identified a novel frameshift mutation of the highly conserved C-terminal domain of MSX1, known as Msx homology domain 6 (MH6), in a Japanese family with non-syndromic tooth agenesis. To investigate the importance of MH6 in tooth development, Msx1 was targeted in mice with CRISPR/Cas system. Although heterozygous MH6 disruption did not alter craniofacial development, homozygous mice exhibited agenesis of lower incisors with or without cleft palate at E16.5. In addition, agenesis of the upper third molars and the lower second and third molars were observed in 4-week-old mutant mice. Although the upper second molars were present, they were abnormally small. These results suggest that the C-terminal domain of MSX1 is important for tooth and palate development, and demonstrate that that CRISPR/Cas system can be used as a tool to assess causality of human disorders in vivo and to study the importance of conserved domains in genes.
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan.|Division of Molecular Biology, Institute of Advanced Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Silvia Naomi
authors.initials: SN
authors.lastname: Mitsui
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yasue
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Masuda
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Naruto
authors.affiliation: Division of Molecular Medicine, Institute of Advanced Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Minegishi
authors.affiliation: Division of Molecular Biology, Institute of Advanced Enzyme Research, Tokushima University, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.affiliation: Tokushima University, 2-24 Shinkura-cho, Tokushima 770-8501, Japan.
authors.forename: Sumihare
authors.initials: S
authors.lastname: Noji
authors.affiliation: Department of Human Genetics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Imoto
authors.affiliation: Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8504, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Tanaka
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D000848:Anodontia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D064113:CRISPR-Cas Systems; D002971:Cleft Lip / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002972:Cleft Palate / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D000072669:Gene Editing / Q000379:methods; D015870:Gene Expression; D056426:Genetic Loci; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007180:Incisor / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism; D051957:MSX1 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008964:Molar, Third / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D009154:Mutation; D010159:Palate / Q000002:abnormalities / Q000254:growth & development / Q000378:metabolism*; D010375:Pedigree; D000072417:Protein Domains
chemical_list: D051957:MSX1 Transcription Factor; C484084:Msx1 protein, mouse