Isolation of a Miller–Dicker lissencephaly gene containing G protein β-subunit-like repeats

Abstract

LISSENCEPHALY (agyria-pachygyria) is a human brain malformation manifested by a smooth cerebral surface and abnormal neuronal migration^1,2. Identification of the gene(s) involved in this disorder would facilitate molecular dissection of normal events in brain development³. Type 1 lissencephaly occurs either as an isolated abnormality or in association with dysmorphic facial appearance in patients with Miller–Dieker syndrome^4,5. 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-l as the disease gene. The deduced amino-acid sequence shows significant homology to β-subunits of heterotrimeric G proteins, suggesting that it could possibly be involved in a signal transduction pathway crucial for cerebral development.