title: An aberrant splice acceptor site due to a novel intronic nucleotide substitution in MSX1 gene is the cause of congenital tooth agenesis in a Japanese family.
abstract: Congenital tooth agenesis is caused by mutations in the MSX1, PAX9, WNT10A, or AXIN2 genes. Here, we report a Japanese family with nonsyndromic tooth agenesis caused by a novel nucleotide substitution in the intronic region between exons 1 and 2 of the MSX1 gene. Because the mutation is located 9 bp before exon 2 (c.452-9G>A), we speculated that the nucleotide substitution would generate an abnormal splice site. Using cDNA analysis of an immortalized patient blood cell, we confirmed that an additional 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). We then studied the subcellular localization of truncated MSX1 protein in COS cells, and observed that it had a whole cell distribution more than a nuclear localization, compared to that of wild-type protein. This result suggests a deletion of the nuclear localization signal, which is mapped to the MSX1 homeodomain. These results indicate that this novel intronic nucleotide substitution is the cause of tooth agenesis in this family. To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations. We here report a rare case of an intronic mutation of the MSX1 gene responsible for human tooth agenesis. In addition, the missing tooth patterns were slightly but significantly different between an affected monozygotic twin pair of this family, showing that epigenetic or environmental factors also affect the phenotypic variations of missing teeth among patients with nonsyndromic tooth agenesis caused by an MSX1 haploinsufficiency.
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan; Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Tatematsu
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan; Department of Dentistry Oral and Maxillofacial Surgery, Ogaki Municipal Hospital, Ogaki, Gifu, Japan; Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan; Department of Oral and Maxillofacial Surgery, Toyota Memorial Hospital, Toyota, Aichi, Japan.
authors.forename: Junichiro
authors.initials: J
authors.lastname: Machida
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan; Department of Dentistry and Oral Surgery, Aichi Children's Health and Medical Center, Obu, Aichi, Japan.
authors.forename: Seishi
authors.initials: S
authors.lastname: Yamaguchi
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan; Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan; Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Goto
authors.affiliation: Department of Embryology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Atsuo
authors.initials: A
authors.lastname: Nakayama
authors.affiliation: Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Higashi
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Miyachi
authors.affiliation: Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Aichi, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Shimozato
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Aichi, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tokita
mesh_terms: D000328:Adult; D000848:Anodontia / Q000000981:diagnostic imaging / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D001483:Base Sequence; D015153:Blotting, Western; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005190:Family; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics*; D051957:MSX1 Transcription Factor / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000235:genetics*; D010375:Pedigree; D022821:RNA Splice Sites / Q000235:genetics*; D012326:RNA Splicing / Q000235:genetics; D011859:Radiography; D013347:Subcellular Fractions / Q000378:metabolism
chemical_list: D018076:DNA, Complementary; D051957:MSX1 Transcription Factor; C484083:MSX1 protein, human; D009711:Nucleotides; D022821:RNA Splice Sites