Nature Genetics
32, 359 - 369 (2002)
Published online: 15 October 2002; | doi:10.1038/ng1009
Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humansKunio Kitamura1, Masako Yanazawa1, Noriyuki Sugiyama2, 3, Hirohito Miura1, Akiko Iizuka-Kogo2, Masatomo Kusaka2, 3, Kayo Omichi1, Rika Suzuki1, Yuko Kato-Fukui1, Kyoko Kamiirisa1, Mina Matsuo1, Shin-ichi Kamijo1, Megumi Kasahara4, Hidefumi Yoshioka3, 4, Tsutomu Ogata5, Takayuki Fukuda6, 7, Ikuko Kondo6, Mitsuhiro Kato8, William B. Dobyns8, Minesuke Yokoyama1
& Ken-ichirou Morohashi2, 31
Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. 2
Department of Developmental Biology, National Institute for Basic Biology, Myodaiji-cho, Okazaki, Japan. 3
Core Research for Evolutional Science and Technology, Japan Science and Technology, Kawaguchi, Saitama, Japan. 4
Department of Natural Sciences, Hyogo University of Teacher Education, Yashiro-cho, Katoh-gun, Japan. 5
Department of Pediatrics, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan. 6
Department of Hygiene, Ehime University School of Medicine, Shitsukawa, Shigenobu, Onsen-gun, Ehime, Japan. 7
Department of Applied Chemistry, Faculty of Engineering, Ehime University, Matsuyama, Japan. 8
Department of Human Genetics, The University of Chicago, Chicago, Illinois, USA.
Correspondence should be addressed to Kunio Kitamura kunio@libra.ls.m-kagaku.co.jpMale embryonic mice with mutations in the X-linked aristaless-related homeobox gene (Arx) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing  -aminobutyric acid (GABAergic interneurons) in the ganglionic eminence and neocortex as well as abnormal testicular differentiation. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia (XLAG) in humans. We found multiple loss-of-function mutations in ARX in individuals affected with XLAG and in some female relatives, and conclude that mutation of ARX causes XLAG. The present report is, to our knowledge, the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.
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