Isolation of a Miller-Dieker lissencephaly gene containing G protein beta-subunit-like repeats.
Lissencephaly (agyria-pachygyria) is a human brain malformation manifested by a smooth cerebral surface and abnormal neuronal migration. Identification of the gene(s) involved in this disorder would facilitate molecular dissection of normal events in brain development. Type 1 lissencephaly occurs either as an isolated abnormality or in association with dysmorphic facial appearance in patients with Miller-Dieker syndrome. About 15% of patients with isolated lissencephaly and more than 90% of patients with Miller-Dieker syndrome have microdeletions in a critical 350-kilobase region in chromosome 17p13.3 (ref. 6). These deletions are hemizygous, so haplo-insufficiency for a gene in this interval is implicated. Here we report the cloning of a gene (LIS-1, lissencephaly-1) in 17p13.3 that is deleted in Miller-Dieker patients. Non-overlapping deletions involving either the 5' or 3' end of the gene were found in two patients, identifying LIS-1 as the disease gene. The deduced amino-acid sequence shows significant homology to beta-subunits of heterotrimeric G proteins, suggesting that it could possibly be involved in a signal transduction pathway crucial for cerebral development.
Reiner
O
O
Institute for Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030.
Carrozzo
R
R
Shen
Y
Y
Wehnert
M
M
Faustinella
F
F
Dobyns
W B
WB
Caskey
C T
CT
Ledbetter
D H
DH
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000002:abnormalities*; D002886:Chromosomes, Human, Pair 17; D003001:Cloning, Molecular; D000013:Congenital Abnormalities / Q000235:genetics; D019204:GTP-Binding Proteins / Q000235:genetics*; D006801:Humans; D006822:Hybrid Cells; D017404:In Situ Hybridization, Fluorescence; D051379:Mice; D008969:Molecular Sequence Data; D012091:Repetitive Sequences, Nucleic Acid; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
D019204:GTP-Binding Proteins