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. 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.

The DISC locus in psychiatric illness

“…In MillerDieker syndrome, lissencephaly results, in part, from disruption of the LIS1 gene. 139,140 In the absence of the Miller-Dieker syndrome, chromosomal deletion, mutations in LIS1 cause a less severe disorder termed isolated lissencephaly sequence (for a review, see Kato and Dobyns 141 ).…”

LIS1—no more no less

“…In humans, lissencephaly has been shown to be caused by mutations in either the genes for Doublecortin (DCX) which is Xlinked 2,3 or LIS1. 4 The mutations usually involve deletions in one allele of the LIS1 gene implying dosage sensitivity for the gene product. 4,5 Subsequently, point mutations were detected as well.…”

“…4 The mutations usually involve deletions in one allele of the LIS1 gene implying dosage sensitivity for the gene product. 4,5 Subsequently, point mutations were detected as well. [6][7][8] In addition, a patient with an in-frame N-terminal deletion was Correspondence: Dr O Reiner, Department of Molecular Genetics, The Weizmann Institute of Science, 76100 Rehovot, Israel.…”

“…We have detected an interaction between LIS1 and Doublecortin (DCX). 41 Mutations in two different genes may result in type I lissencephaly: LIS1, 4 and doublecortin, an X-linked gene. 2,3 The phenotypic presentation of the patients is very similar.…”

Interaction between neurone and microglia mediated by platelet‐activating factor

“…PAF is also apparently relevant to brain development, since the beta subunit of the PAF inactivating enzyme, bovine PAF acetylhydrolase (PAF-AH), has 99% homology with the human lis-1 gene. The gene codes for a protein related to Miller±Dieker lissencephaly, an inherited neurological disorder that is characterized by the lack of gyri and sulci in the cerebral cortex (Reiner et al 1993;Hattori et al 1994). Taken together, these observations strongly suggest that PAF plays crucial roles in the central nervous system.…”