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Human Molecular Genetics, 2003, Vol. 12, No. 12 1449-1459
DOI: 10.1093/hmg/ddg153
© 2003 Oxford University Press

Fukutin is required for maintenance of muscle integrity, cortical histiogenesis and normal eye development

Satoshi Takeda1, Mari Kondo1, Junko Sasaki2, Hiroki Kurahashi2, Hiroki Kano2, Ken Arai3, Kazuyo Misaki4, Takehiko Fukui5, Kazuhiro Kobayashi2, Masaji Tachikawa2, Michihiro Imamura6, Yusuke Nakamura7, Teruo Shimizu3, Tatsufumi Murakami8, Yoshihide Sunada8, Takashi Fujikado5, Kiichiro Matsumura3, Toshio Terashima4 and Tatsushi Toda2,*

1Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan, 2Division of Functional Genomics, Department of Post-Genomics and Diseases, Osaka University Graduate School of Medicine, 2-2-B9 Yamadaoka, Suita, Osaka 565-0871, Japan, 3Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan, 4Department of Anatomy and Neurobiology, Kobe University Graduate School of Medicine, Kobe, Japan, 5Department of Ophthalmology and Visual Science, Osaka University Graduate School of Medicine, Osaka, Japan, 6Institute of Neuroscience, National Center for Neurology and Psychiatry, Tokyo, Japan, 7Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan and 8Department of Neurology, Kawasaki Medical School, Kurashiki, Japan

Received December 5, 2002; Revised March 21, 2003; Accepted April 10, 2003

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal-recessive disorders in Japan, is characterized by congenital muscular dystrophy associated with brain malformation due to a defect during neuronal migration. Through positional cloning, we previously identified the gene for FCMD, which encodes the fukutin protein. Here we report that chimeric mice generated using embryonic stem cells targeted for both fukutin alleles develop severe muscular dystrophy, with the selective deficiency of {alpha}-dystroglycan and its laminin-binding activity. In addition, these mice showed laminar disorganization of the cortical structures in the brain with impaired laminin assembly, focal interhemispheric fusion, and hippocampal and cerebellar dysgenesis. Further, chimeric mice showed anomaly of the lens, loss of laminar structure in the retina, and retinal detachment. These results indicate that fukutin is necessary for the maintenance of muscle integrity, cortical histiogenesis, and normal ocular development and suggest the functional linkage between fukutin and {alpha}-dystroglycan.

* To whom correspondence should be addressed. Tel: +81 668793380; Fax: +81 668793389; Email: toda{at}clgene.med.osaka-u.ac.jp


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