Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans

Kunio Kitamura; Masako Yanazawa; Noriyuki Sugiyama; Hirohito Miura; Akiko Iizuka-Kogo; Masatomo Kusaka; Kayo Omichi; Rika Suzuki; Yuko Kato-Fukui; Kyoko Kamiirisa; Mina Matsuo; Shin Ichi Kamijo; Megumi Kasahara; Hidefumi Yoshioka; Tsutomu Ogata; Takayuki Fukuda; Ikuko Kondo; Mitsuhiro Kato; William B. Dobyns; Minesuke Yokoyama; Ken Ichirou Morohashi

doi:10.1038/ng1009

Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans

Kunio Kitamura, Masako Yanazawa, Noriyuki Sugiyama, Hirohito Miura, Akiko Iizuka-Kogo, Masatomo Kusaka, Kayo Omichi, Rika Suzuki, Yuko Kato-Fukui, Kyoko Kamiirisa, Mina Matsuo, Shin Ichi Kamijo, Megumi Kasahara, Hidefumi Yoshioka, Tsutomu Ogata, Takayuki Fukuda, Ikuko Kondo, Mitsuhiro Kato, William B. Dobyns, Minesuke YokoyamaKen Ichirou Morohashi

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Abstract

Male 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 γ-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.

Original language	English (US)
Pages (from-to)	359-369
Number of pages	11
Journal	Nature Genetics
Volume	32
Issue number	3
DOIs	https://doi.org/10.1038/ng1009
State	Published - Nov 1 2002
Externally published	Yes

Bibliographical note

Funding Information:
The authors thank L.R. Rubenstein for providing Titf1; M. Price for Dlx1; V. Pachnis for Lhx6; J. Mason for Wntb8; S. Retaux for Lhx9; B. Condie, C. Gerfen and Y. Yanagawa for Gad1; I. Mason for antibody against Hsd3b1; Y. Motegi, Y. Nakahara, A. Suehiro, T. Akiyama, A. Miyake, A. Oshida and A. Ohwaki for technical support; Y. Arimatsu, H. Takahashi, S. Tanaka and B. Capel for helpful discussion; H. Nakamura and H. Okamoto for their encouragement; and the parents of children with XLAG who were studied. This work was supported in part by grants-in-aid for scientific research to K.M. from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from the US National Institutes of Health to W.B.D.

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Kitamura, K., Yanazawa, M., Sugiyama, N., Miura, H., Iizuka-Kogo, A., Kusaka, M., Omichi, K., Suzuki, R., Kato-Fukui, Y., Kamiirisa, K., Matsuo, M., Kamijo, S. I., Kasahara, M., Yoshioka, H., Ogata, T., Fukuda, T., Kondo, I., Kato, M., Dobyns, W. B., ... Morohashi, K. I. (2002). Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans. Nature Genetics, 32(3), 359-369. https://doi.org/10.1038/ng1009

Kitamura, K, Yanazawa, M, Sugiyama, N, Miura, H, Iizuka-Kogo, A, Kusaka, M, Omichi, K, Suzuki, R, Kato-Fukui, Y, Kamiirisa, K, Matsuo, M, Kamijo, SI, Kasahara, M, Yoshioka, H, Ogata, T, Fukuda, T, Kondo, I, Kato, M, Dobyns, WB, Yokoyama, M & Morohashi, KI 2002, 'Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans', Nature Genetics, vol. 32, no. 3, pp. 359-369. https://doi.org/10.1038/ng1009

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title = "Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans",

abstract = "Male 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 γ-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.",

author = "Kunio Kitamura and Masako Yanazawa and Noriyuki Sugiyama and Hirohito Miura and Akiko Iizuka-Kogo and Masatomo Kusaka and Kayo Omichi and Rika Suzuki and Yuko Kato-Fukui and Kyoko Kamiirisa and Mina Matsuo and Kamijo, {Shin Ichi} and Megumi Kasahara and Hidefumi Yoshioka and Tsutomu Ogata and Takayuki Fukuda and Ikuko Kondo and Mitsuhiro Kato and Dobyns, {William B.} and Minesuke Yokoyama and Morohashi, {Ken Ichirou}",

note = "Funding Information: The authors thank L.R. Rubenstein for providing Titf1; M. Price for Dlx1; V. Pachnis for Lhx6; J. Mason for Wntb8; S. Retaux for Lhx9; B. Condie, C. Gerfen and Y. Yanagawa for Gad1; I. Mason for antibody against Hsd3b1; Y. Motegi, Y. Nakahara, A. Suehiro, T. Akiyama, A. Miyake, A. Oshida and A. Ohwaki for technical support; Y. Arimatsu, H. Takahashi, S. Tanaka and B. Capel for helpful discussion; H. Nakamura and H. Okamoto for their encouragement; and the parents of children with XLAG who were studied. This work was supported in part by grants-in-aid for scientific research to K.M. from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from the US National Institutes of Health to W.B.D.",

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AU - Kitamura, Kunio

AU - Yanazawa, Masako

AU - Sugiyama, Noriyuki

AU - Miura, Hirohito

AU - Iizuka-Kogo, Akiko

AU - Kusaka, Masatomo

AU - Omichi, Kayo

AU - Suzuki, Rika

AU - Kato-Fukui, Yuko

AU - Kamiirisa, Kyoko

AU - Matsuo, Mina

AU - Kamijo, Shin Ichi

AU - Kasahara, Megumi

AU - Yoshioka, Hidefumi

AU - Ogata, Tsutomu

AU - Fukuda, Takayuki

AU - Kondo, Ikuko

AU - Kato, Mitsuhiro

AU - Dobyns, William B.

AU - Yokoyama, Minesuke

AU - Morohashi, Ken Ichirou

N1 - Funding Information: The authors thank L.R. Rubenstein for providing Titf1; M. Price for Dlx1; V. Pachnis for Lhx6; J. Mason for Wntb8; S. Retaux for Lhx9; B. Condie, C. Gerfen and Y. Yanagawa for Gad1; I. Mason for antibody against Hsd3b1; Y. Motegi, Y. Nakahara, A. Suehiro, T. Akiyama, A. Miyake, A. Oshida and A. Ohwaki for technical support; Y. Arimatsu, H. Takahashi, S. Tanaka and B. Capel for helpful discussion; H. Nakamura and H. Okamoto for their encouragement; and the parents of children with XLAG who were studied. This work was supported in part by grants-in-aid for scientific research to K.M. from the Ministry of Education, Science, Sports, and Culture of Japan and by a grant from the US National Institutes of Health to W.B.D.

PY - 2002/11/1

Y1 - 2002/11/1

N2 - Male 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 γ-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.

AB - Male 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 γ-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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Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans

Abstract

Bibliographical note

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