title: Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development.
abstract: Human brain malformations, such as Miller-Dieker syndrome (MDS) or isolated lissencephaly sequence (ILS) may result from abnormal neuronal migration during brain development. MDS and ILS patients have a hemizygous deletion or mutation in the LIS1 gene (PAFAH1B1), therefore, the LIS1 encoded protein (Lis1) may play a role in neuronal migration. Lis1 is a subunit of a brain platelet-activating factor acetylhydrolase (PAFAH1B) where it forms a heterotrimeric complex with two hydrolase subunits, referred to as 29 kDa (PAFAH1B3) and 30 kDa (PAFAH1B2). In order to determine whether this heterotrimer is required for the developmental functions of PAFAH1B, we examined the binding properties of 29 and 30 kDa subunits to mutant Lis1 proteins. The results defined the critical regions of Lis1 for PAFAH1B complex formation and demonstrated that all human LIS1 mutations examined resulted in abolished or reduced capacity of Lis1 to interact with the 29 and 30 kDa subunits, suggesting that the PAFAH1B complex participates in the process of neuronal migration.
authors.affiliation: Max Planck Institute for Experimental Endocrinology, Feodor-Lynen Strasse 7, D-30625, Hannover, Germany.
authors.forename: K J
authors.initials: KJ
authors.lastname: Sweeney
authors.forename: G D
authors.initials: GD
authors.lastname: Clark
authors.forename: A
authors.initials: A
authors.lastname: Prokscha
authors.forename: W B
authors.initials: WB
authors.lastname: Dobyns
authors.forename: G
authors.initials: G
authors.lastname: Eichele
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D001921:Brain / Q000254:growth & development*; D019281:Dimerization; D005982:Glutathione Transferase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010741:Phospholipases A / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D020449:Repetitive Sequences, Amino Acid; D020798:Two-Hybrid System Techniques
chemical_list: D008869:Microtubule-Associated Proteins; D011994:Recombinant Proteins; D005982:Glutathione Transferase; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C084102:PAFAH1B1 protein, human