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Classical lissencephaly (smooth brain) or generalized agyriapachygyria is a severe brain malformation which results from an arrest of neuronal migration at 9–13 weeks gestation. It has been observed in several malformation syndromes including Miller-Dieker syndrome (MDS) and isolated lissencephaly sequence (ILS). A gene containing β-transducin like repeats, now known as  LIS1 , was previously mapped to the ILS/MDS chromosome region on 17p13.3. We recently localized the classical lissencephaly critical region to the  LIS1  gene locus by molecular analysis of key ILS and MDS patients. We have now characterized the structure of  LIS1 , which consists of 11 exons, and have searched for the presence of subtle mutations in 19 ILS patients who showed no gross rearrangements of  LIS1 . Single strand conformational polymorphism (SSCP) analysis revealed band-shifts for three patients, each involving a different coding exon, which were not observed in their respective parental DNAs. Sequence analysis identified these  de novo  mutations as a dA→dG transition in exon VI at nucleotide 446, a dC→dT transition in exon VIII at nucleotide 817, and a 22 bp deletion at the exon IX-intron 9 junction from nucleotide 988 to 1002+7, which causes skipping of exon IX in the mature LIS1 transcript. These changes are predicted to result in an H149R amino acid substitution, an R273X premature translation termination, and abolition of amino acids 301–334, in the respective LIS1 proteins. These data thus confirm  LIS1  as the gene responsible for classical lissencephaly in ILS and MDS.

Point Mutations and an Intragenic Deletion in LIS1 , the Lissencephaly Causative Gene in Isolated Lissencephaly Sequence and Miller-Dieker Syndrome