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

Nat Genet. 2002 Nov;32(3):359-69. doi: 10.1038/ng1009. Epub 2002 Oct 15.

Affiliation

¹ Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. kunio@libra.ls.m-kagaku.co.jp

PMID: 12379852
DOI: 10.1038/ng1009

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 gamma-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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Alleles
Amino Acid Sequence
Animals
Apoptosis
Base Sequence
Brain / abnormalities
Brain / pathology
Bromodeoxyuridine / pharmacology
Cell Differentiation
Cell Division
Cell Movement
DNA, Complementary / metabolism
Doublecortin Protein
Epithelial Cells / metabolism
Genetic Linkage*
Genetic Vectors
Genitalia / abnormalities*
Homeodomain Proteins / genetics*
Homeodomain Proteins / physiology*
Humans
Immunohistochemistry
Male
Mice
Mice, Knockout
Microscopy, Fluorescence
Models, Genetic
Molecular Sequence Data
Mutation*
Neurons / metabolism
Neurons / pathology
Phenotype
Prosencephalon / abnormalities*
Syndrome
Testis / abnormalities*
Testis / pathology
Transcription Factors / genetics*
Transcription Factors / physiology*
Transfection
X Chromosome / genetics*

Substances

ARX protein, human
ARX protein, mouse
DNA, Complementary
Dcx protein, mouse
Doublecortin Protein
Homeodomain Proteins
Transcription Factors
Bromodeoxyuridine

Associated data

GENBANK/AB006103
GENBANK/AC002504
GENBANK/AY038071