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Novel nonsense mutation in MSX1 in familial nonsyndromic oligodontia: subcellular localization and role of homeodomain/MH4

Authors

  • Masashi Kimura,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
    2. Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Japan
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  • Junichiro Machida,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
    2. Department of Oral and Maxillofacial Surgery, Toyota Memorial Hospital, Toyota, Japan
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  • Seishi Yamaguchi,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
    2. Department of Dentistry and Oral Surgery, Aichi Children's Health and Medical Center, Obu, Japan
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  • Akio Shibata,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
    2. Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Japan
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  • Tadashi Tatematsu,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
    2. Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Japan
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  • Hitoshi Miyachi,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
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  • Peter A. Jezewski,

    1. Department of Periodontology, Institute of Oral Health Research, University of Alabama at Birmingham School of Dentistry, Birmingham, AL, USA
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  • Atsuo Nakayama,

    1. Department of Embryology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Japan
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  • Yujiro Higashi,

    1. Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Japan
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  • Kazuo Shimozato,

    1. Department of Maxillofacial Surgery, Aichi-Gakuin University School of Dentistry, Nagoya, Japan
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  • Yoshihito Tokita

    Corresponding author
    1. Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kasugai, Japan
    • Yoshihito Tokita, Department of Perinatology, Institute for Developmental Research, Aichi-Human Service Center, Kamiya, 713-8, Kasugai, Aichi 480-0392, Japan

      E-mail: tokita@inst-hsc.jp

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Abstract

Nonsyndromic tooth agenesis is one of the most common anomalies in human development. Part of the malformation is inherited and is associated with paired box 9 (PAX9), msh homeobox 1 (MSX1), and axin 2 (AXIN2) mutations. To obtain a comprehensive understanding of the genetic and molecular mechanisms that underlie this genetic disease, we investigated six familial and seven sporadic Japanese cases of nonsyndromic tooth agenesis. Searches for mutations in these candidate genes detected a novel nonsense mutation (c.416G>A) in exon 1 of MSX1 from a family with oligodontia. This mutation co-segregated in the affected family members. Moreover, this mutation produced a termination codon in the first exon and therefore the gene product (W139X) was truncated at the C terminus, hence, the entire homeodomain/MH4, which has many functions, such as DNA binding, protein-protein interaction, and nuclear localization, was absent. We characterized the properties of this truncated MSX1 by investigating the subcellular localization of the mutant gene product in transfected cells. The wild-type MSX1 localized exclusively at the nuclear periphery of transfected cells, whereas the mutant MSX1 was stable but localized diffusely throughout the whole cell. These results indicate that W139X MSX1 is responsible for tooth agenesis.

Ancillary