title: Intracellular levels of the LIS1 protein correlate with clinical and neuroradiological findings in patients with classical lissencephaly.
abstract: We report on the genotype-phenotype correlation in 7 patients with classical lissencephaly carrying a heterozygous subtle mutation in the LIS1 gene. Six patients, showed a mutation predicted to encode for 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 patients bearing truncating mutations indicated that the mutated allele did not produce a detectable amount of the LIS1 protein; whereas the analysis performed on the fibroblasts from the patient with a splice-site mutation was suggestive of partial protein synthesis from the mutated allele. Although clinical and magnetic resonance imaging findings of patients with truncating mutations did not differ from those observed in patients with a heterozygous deletion, the patient bearing the exon-skipping mutation had less severe clinical and brain involvement. Our data suggest that truncating mutations in the LIS1 gene are relatively common among patients with classical lissencephaly not bearing a heterozygous deletion at 17p13.3, and strengthen the relevance of correct intracellular dosage of the LIS1 protein in the neuronal migration process.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), San Raffaele Biomedical Science Park, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Fogli
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: F
authors.initials: F
authors.lastname: Moro
authors.forename: E
authors.initials: E
authors.lastname: Fernandez-Alvarez
authors.forename: M O
authors.initials: MO
authors.lastname: Livet
authors.forename: A
authors.initials: A
authors.lastname: Renieri
authors.forename: M
authors.initials: M
authors.lastname: Cioni
authors.forename: D T
authors.initials: DT
authors.lastname: Pilz
authors.forename: P
authors.initials: P
authors.lastname: Veggiotti
authors.forename: E
authors.initials: E
authors.lastname: Rossi
authors.forename: A
authors.initials: A
authors.lastname: Ballabio
authors.forename: R
authors.initials: R
authors.lastname: Carrozzo
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000483:Alleles; D000595:Amino Acid Sequence; D015153:Blotting, Western; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008869:Microtubule-Associated Proteins; D008969:Molecular Sequence Data; D009154:Mutation; D011506:Proteins / Q000235:genetics*