Lissencephaly associated mutations suggest a requirement for the PAFAH1B heterotrimeric complex in brain development

Kimberley J. Sweeney, Gary D. Clark, Alexander Prokscha, William B. Dobyns, Gregor Eichele

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37 Scopus citations


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. (C) 2000 Elsevier Science Ireland Ltd.

Original languageEnglish (US)
Pages (from-to)263-271
Number of pages9
JournalMechanisms of Development
Issue number2
StatePublished - Apr 1 2000
Externally publishedYes

Bibliographical note

Funding Information:
We wish to thank Dr Urs Albrecht for the mLis1, 29 and 30 kDa yeast two-hybrid constructs, Dr Paul James for the gift of PJ69-4A yeast cells, Uwe Grunenberg for help with sequencing and Dr Richard Lilischkis for his constant and generous advice. This work was supported by The Alexander von Humboldt Foundation (KS) and the following grants NIH NS37146 and NS38289 (GC).


  • 29 kDa
  • 30 kDa
  • Brain development
  • Cortical malformation
  • Heterotrimeric complex
  • LIS1
  • Lissencephaly
  • Miller-Dieker syndrome
  • Mutation
  • Neuronal migration
  • PAFAH1B1
  • PAFAH1B2
  • PAFAH1B3
  • Platelet-activating factor
  • WD40 repeat protein
  • Yeast two-hybrid
  • β-Propeller structure


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