Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly.

We report on the genotype-phenotype correlation in 7 patients with classica l lissencephaly carrying a heterozygous subtle mutation in the LIS1 gene. S ix patients showed a mutation predicted to encode fbr a truncated protein, and one mutation altered a splicing site, resulting in skipping of exon 4. Western blot analysis performed on the lymphoblastoid cell line of 2 patien ts bearing truncating mutations indicated that the mutated allele did not p roduce a detectable amount of the LIS1 protein; whereas the analysis perfor med on the fibroblasts from the patient with a splice-site mutation was sug gestive of partial protein synthesis from the mutated allele. Although clin ical and magnetic resonance imaging findings of patients with truncating mu tations did not differ from those observed in patients with a heterozygous deletion, the patient bearing the exon-skipping mutation had less severe cl inical and brain involvement. Our data suggest that truncating mutations in the LIS1 gene are relatively common among patients with classical lissence phaly not bearing a heterozygous deletion at 17p13.3, and strengthen the re levance of correct intracellular dosage of the LIS1 protein in the neuronal migration process.