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Aristaless-related homeobox gene disruption leads to abnormal distribution of GABAergic interneurons in human neocortex: evidence based on a case of X-linked lissencephaly with abnormal genitalia (XLAG)

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Abstract

X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene, located on Xp22.13. Arx-null mice show loss of tangential migration of GABAergic interneurons, presumably being related to caudal ganglionic eminence tangential migration. In the present study, we investigated a subpopulation of GABAergic interneurons in the brain of an infant with XLAG, who had a novel nonsense mutation of the ARX gene, compared with those of age-matched normal controls and Miller–Dieker syndrome. We performed immunocytochemistry for interneuron and migration markers. We found that glutamic acid decarboxylase (GAD)- and calretinin (CR)-containing cells were significantly reduced in the neocortex and located in the white matter and neocortical subventricular zone, while neuropeptide Y- or cholecystokinin-containing cells were normally distributed. Moreover, in the neocortical subventricular region, the GAD- and CR-containing cells expressed the radial migration marker Mash-1 as well as nestin. Our findings suggest that ARX protein controls not only the tangential migration of GABAergic interneurons from the ganglionic eminence, but also may serve to induce radial migration from the neocortical subventricular zone.

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Acknowledgments

We thank Dr. J. E. Johnson, University of Texas Southwestern Medical Center, for providing the antibodies for Mash-1 and NGN-1, and Mr. S. Kumagai, National Center of Neurology and Psychiatry, for technical assistance. This study was supported by grants from the Ministry of Health, Welfare and Labor, and the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Department of Pediatric Neurology, Osaka City General Hospital, Osaka, Japan

    Shin Okazaki, Ichiro Kuki, Hisashi Kawawaki & Kiyotaka Tomiwa

  2. Department of Mental Retardation and Birth Defect Research, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo, 187-8502, Japan

    Maki Ohsawa, Yu-ichi Goto, Kunio Kitamura & Masayuki Itoh

  3. Department of Neonatology, Osaka City General Hospital, Osaka, Japan

    Takeshi Koriyama, Shingou Ri & Hiroyuki Ichiba

  4. Department of Pathology, Osaka City General Hospital, Osaka, Japan

    Eishu Hai & Takeshi Inoue

  5. Department of Obstetrics, Osaka City General Hospital, Osaka, Japan

    Hiroaki Nakamura

  6. Genetic Counseling and Clinical Research Unit, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Kiyotaka Tomiwa

  7. Department of Pediatrics, Faculty of Medicine, Osaka Municipal University, Osaka, Japan

    Tsunekazu Yamano

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  1. Shin Okazaki
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Corresponding author

Correspondence to Masayuki Itoh.

Additional information

Shin Okazaki and Masayuki Itoh contributed equally to this work.

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Okazaki, S., Ohsawa, M., Kuki, I. et al. Aristaless-related homeobox gene disruption leads to abnormal distribution of GABAergic interneurons in human neocortex: evidence based on a case of X-linked lissencephaly with abnormal genitalia (XLAG). Acta Neuropathol 116, 453–462 (2008). https://doi.org/10.1007/s00401-008-0382-2

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  • DOI: https://doi.org/10.1007/s00401-008-0382-2

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