An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy

Kazuhiro Kobayashi, Yutaka Nakahori, Masashi Miyake, Kiichiro Matsumura, Eri Kondo-Iida, Yoshiko Nomura, Masaya Segawa, Mieko Yoshioka, Kayoko Saito, Makiko Osawa, Kenzo Hamano, Youichi Sakakihara, Ikuya Nonaka, Yasuo Nakagome, Ichiro Kanazawa, Yusuke Nakamura, Katsushi Tokunaga and Tatsushi Toda ()
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Kazuhiro Kobayashi: Laboratories of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo
Yutaka Nakahori: School of Medicine, University of Tokushima
Masashi Miyake: Graduate School of Medicine, University of Tokyo
Kiichiro Matsumura: Teikyo University School of Medicine
Eri Kondo-Iida: Laboratories of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo
Yoshiko Nomura: Segawa Neurological Clinic for Children
Masaya Segawa: Segawa Neurological Clinic for Children
Mieko Yoshioka: Kobe General Hospital
Kayoko Saito: Tokyo Women's Medical College
Makiko Osawa: Tokyo Women's Medical College
Kenzo Hamano: Institute of Clinical Medicine, University of Tsukuba
Youichi Sakakihara: Graduate School of Medicine, University of Tokyo
Ikuya Nonaka: National Institute of Neuroscience, NCNP
Yasuo Nakagome: Graduate School of Medicine, University of Tokyo
Ichiro Kanazawa: Graduate School of Medicine, University of Tokyo
Yusuke Nakamura: Laboratories of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo
Katsushi Tokunaga: Graduate School of Medicine, University of Tokyo
Tatsushi Toda: Laboratories of Genome Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo

Nature, 1998, vol. 394, issue 6691, 388-392

Abstract: 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.

Date: 1998
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DOI: 10.1038/28653

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