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An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy

Nature volume 394, pages 388–392 (1998)Cite this article

Abstract

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7–1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micro-polygria) due to a defect in the migration of neurons1. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31 (2–4). We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor5. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3′ untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.

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Figure 1: Genomic insertion in FCMD patients.
Figure 2: Amino-acid sequence of the protein (fukutin) encoded by of the FCMD gene.
Figure 3: Northern blot analysis of the FCMD gene.
Figure 4: Segregation of point mutations in the families of H.M. and T.I.
Figure 5: Cellular localization of fukutin.

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Acknowledgements

We thank the family members who participated in this study; F. Saito, Y. Sunada, E.Katayama, M. Hino, J. Fujisawa, F. Oyama, I. Nishino, H. Hohjoh, Y. Miki, M. Watanabe, T. Tokino, K.Arahata, Y. Fukuda, J. Inazawa, T. Tanaka and S. Ikegawa for advice; T. Iwata, T. Kumagai, S. Kobayashi, T. Ishihara, K. Suzumori, C. Nakano, S. Sugino, M. Funahashi, Y. Mizuno, H. Muranaka, A. Honma and E.Nanba for samples; J. Goto and N. Tsuji for managing cell lines; and I. Matsushita and K. Takeuchi for technical assistance. This work was supported by grants from the Ministry of Health and Welfare and from the Ministry of Education, Science and Culture, Japan.

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Authors and Affiliations

  1. Laboratories of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Kazuhiro Kobayashi, Eri Kondo-Iida & Tatsushi Toda

  2. Laboratories of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, 108-8639, Tokyo, Japan

    Yusuke Nakamura

  3. Departments of Human Genetics, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033, Japan

    Kazuhiro Kobayashi, Masashi Miyake, Yasuo Nakagome & Katsushi Tokunaga

  4. Departments of Pediatrics, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033, Japan

    Youichi Sakakihara

  5. Departments of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, 113-0033, Japan

    Ichiro Kanazawa

  6. Department of Public Health, School of Medicine, University of Tokushima, Tokushima, 770-8503, Japan

    Yutaka Nakahori

  7. Department of Neurology, Teikyo University School of Medicine, Tokyo, 173-8605, Japan

    Kiichiro Matsumura

  8. Department of Pediatrics, Tokyo Women's Medical College, Tokyo, 162-8666, Japan

    Eri Kondo-Iida, Kayoko Saito & Makiko Osawa

  9. Segawa Neurological Clinic for Children, Tokyo, 101-0062, Japan

    Yoshiko Nomura & Masaya Segawa

  10. Department of Pediatrics, Kobe General Hospital, Kobe, 650-0046, Japan

    Mieko Yoshioka

  11. Department of Pediatrics, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, 305-8576, Japan

    Kenzo Hamano

  12. Department of Ultrastructural Research, National Institute of Neuroscience, NCNP, Tokyo, 187-8502, Japan

    Ikuya Nonaka

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  1. Kazuhiro Kobayashi
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  18. Tatsushi Toda
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Corresponding author

Correspondence to Tatsushi Toda.

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Kobayashi, K., Nakahori, Y., Miyake, M. et al. An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy. Nature 394, 388–392 (1998). https://doi.org/10.1038/28653

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