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

• Published in: Nature (London) Vol. 364; no. 6439; pp. 717 - 721
• Main Authors: REINER, O, CARROZZO, R, YING SHEN, WEHNERT, M, FAUSTINELLA, F, DOBYNS, W. B, CASKEY, C. T, LEDBETTER, D. H
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 19-08-1993; Nature Publishing Group
• Subjects: Amino Acid Sequence; Animals; Biochemistry; Biological and medical sciences; Brain; Brain - abnormalities; Chromosomes, Human, Pair 17; Cloning; Cloning, Molecular; Congenital Abnormalities - genetics; Disease; Genes; GTP-Binding Proteins - genetics; Humans; Hybrid Cells; In Situ Hybridization, Fluorescence; Malformations of the nervous system; Medical sciences; Mice; Molecular Sequence Data; Neurology; Repetitive Sequences, Nucleic Acid; Sequence Homology, Amino Acid; Signal Transduction; Human; Nervous system diseases; Gene; Lissencephaly; Malformation; Analog; Beta-Peptide chain; Deletion; Molecular cloning; Cerebral disorder; G protein
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/364717a0

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.