title: Analysis of lissencephaly-causing LIS1 mutations.
abstract: Mutations in the LIS1 gene may result in severe abnormalities of brain cortical layering known as lissencephaly. Most lissencephaly-causing LIS1 mutations are deletions that encompass the entire gene, therefore the mechanism of the disease is regarded as haploinsufficiency. So far, 13 different intragenic mutations have been reported: one point mutation, H149R; deletion of exon 9, which results in deleted acids Delta301-334; deletion of exon 4, which results in deleted amino acids Delta40-64; 10 mutations resulting in truncated proteins and one predicted to result in extra amino acids. We studied the consequences of the point mutation, deletion mutation and one of the reported truncations. In order to study LIS1 structure function, we introduced an additional point mutation and other truncations in different regions of the protein. The consequences of these mutations to protein folding were studied by gel filtration, sucrose density gradient centrifugation and measuring resistance to trypsin cleavage. On the basis of our results, we suggest that all truncation mutations and lissencephaly-causing point mutations or internal deletion result in a reduction in the amount of correctly folded LIS1 protein.
authors.affiliation: Department of Molecular Genetics, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Sapir
authors.forename: M
authors.initials: M
authors.lastname: Eisenstein
authors.forename: H A
authors.initials: HA
authors.lastname: Burgess
authors.forename: D
authors.initials: D
authors.lastname: Horesh
authors.forename: A
authors.initials: A
authors.lastname: Cahana
authors.forename: J
authors.initials: J
authors.lastname: Aoki
authors.forename: M
authors.initials: M
authors.lastname: Hattori
authors.forename: H
authors.initials: H
authors.lastname: Arai
authors.forename: K
authors.initials: K
authors.lastname: Inoue
authors.forename: O
authors.initials: O
authors.lastname: Reiner
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000002:abnormalities*; D002417:Cattle; D003198:Computer Simulation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D017354:Point Mutation; D017510:Protein Folding; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D017384:Sequence Deletion; D017386:Sequence Homology, Amino Acid
chemical_list: D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human; C513190:Pafah1b1 protein, mouse