title: LIS1 missense mutations: variable phenotypes result from unpredictable alterations in biochemical and cellular properties.
abstract: Mutations in one allele of the human LIS1 gene cause a severe brain malformation, lissencephaly. Although most LIS1 mutations involve deletions, several point mutations with a single amino acid alteration were described. Patients carrying these mutations reveal variable phenotypic manifestations. We have analyzed the functional importance of these point mutations by examining protein stability, folding, intracellular localization, and protein-protein interactions. Our data suggest that the mutated proteins were affected at different levels, and no single assay could be used to predict the lissencephaly phenotype. Most interesting are those mutant proteins that retain partial folding and interactions. In the case of LIS1 mutated in F31S, the cellular phenotype may be modified by overexpression of specific interacting proteins. Overexpression of the PAF-AH alpha1 subunit dissolved aggregates induced by this mutant protein and increased its half-life. Overexpression of NudE or NudEL localized this mutant protein to spindle poles and kinetochores but had no effect on protein stability. Our results implicate that there are probably different biochemical and cellular mechanisms obstructed in each patient yielding the varied lissencephaly phenotypes.
authors.affiliation: Department of Molecular Genetics, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Caspi
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Coquelle
authors.forename: Cynthia
authors.initials: C
authors.lastname: Koifman
authors.forename: Talia
authors.initials: T
authors.lastname: Levy
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.forename: Jan R
authors.initials: JR
authors.lastname: De Mey
authors.forename: Orly
authors.initials: O
authors.lastname: Reiner
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001921:Brain / Q000002:abnormalities*; D002460:Cell Line; D006367:HeLa Cells; D006801:Humans; D008856:Microscopy, Fluorescence; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics*; D008957:Models, Genetic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D017354:Point Mutation; D011233:Precipitin Tests; D011485:Protein Binding; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D014162:Transfection; D014357:Trypsin / Q000494:pharmacology; D020798:Two-Hybrid System Techniques
chemical_list: D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; D014357:Trypsin