Mutation of ARX causes abnormal development of forebrain and testes in mice and X-linked lissencephaly with abnormal genitalia in humans.
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.
Kitamura
Kunio
K
Mitsubishi Kagaku Institute of Life Sciences, 11 Minamiooya, Machida, Tokyo 194-8511, Japan. kunio@libra.ls.m-kagaku.co.jp
Yanazawa
Masako
M
Sugiyama
Noriyuki
N
Miura
Hirohito
H
Iizuka-Kogo
Akiko
A
Kusaka
Masatomo
M
Omichi
Kayo
K
Suzuki
Rika
R
Kato-Fukui
Yuko
Y
Kamiirisa
Kyoko
K
Matsuo
Mina
M
Kamijo
Shin-ichi
S
Kasahara
Megumi
M
Yoshioka
Hidefumi
H
Ogata
Tsutomu
T
Fukuda
Takayuki
T
Kondo
Ikuko
I
Kato
Mitsuhiro
M
Dobyns
William B
WB
Yokoyama
Minesuke
M
Morohashi
Ken-ichirou
K
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D001921:Brain / Q000002:abnormalities / Q000473:pathology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D002455:Cell Division; D002465:Cell Movement; D018076:DNA, Complementary / Q000378:metabolism; D000089662:Doublecortin Protein; D004847:Epithelial Cells / Q000378:metabolism; D008040:Genetic Linkage; D005822:Genetic Vectors; D005835:Genitalia / Q000002:abnormalities*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D016548:Prosencephalon / Q000002:abnormalities*; D013577:Syndrome; D013737:Testis / Q000002:abnormalities* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014162:Transfection; D014960:X Chromosome / Q000235:genetics*
C469264:ARX protein, human; C469265:ARX protein, mouse; D018076:DNA, Complementary; C000714847:Dcx protein, mouse; D000089662:Doublecortin Protein; D018398:Homeodomain Proteins; D014157:Transcription Factors; D001973:Bromodeoxyuridine