Increased LIS1 expression affects human and mouse brain development

Nat Genet. 2009 Feb;41(2):168-77. doi: 10.1038/ng.302. Epub 2009 Jan 11.


Deletions of the PAFAH1B1 gene (encoding LIS1) in 17p13.3 result in isolated lissencephaly sequence, and extended deletions including the YWHAE gene (encoding 14-3-3epsilon) cause Miller-Dieker syndrome. We identified seven unrelated individuals with submicroscopic duplication in 17p13.3 involving the PAFAH1B1 and/or YWHAE genes, and using a 'reverse genomics' approach, characterized the clinical consequences of these duplications. Increased PAFAH1B1 dosage causes mild brain structural abnormalities, moderate to severe developmental delay and failure to thrive. Duplication of YWHAE and surrounding genes increases the risk for macrosomia, mild developmental delay and pervasive developmental disorder, and results in shared facial dysmorphologies. Transgenic mice conditionally overexpressing LIS1 in the developing brain showed a decrease in brain size, an increase in apoptotic cells and a distorted cellular organization in the ventricular zone, including reduced cellular polarity but preserved cortical cell layer identity. Collectively, our results show that an increase in LIS1 expression in the developing brain results in brain abnormalities in mice and humans.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / genetics*
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / metabolism
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase / physiology*
  • Adolescent
  • Animals
  • Base Sequence
  • Brain / embryology*
  • Brain / growth & development
  • Child
  • Child, Preschool
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 17
  • Classical Lissencephalies and Subcortical Band Heterotopias / genetics
  • Embryo, Mammalian
  • Female
  • Gene Duplication
  • Gene Expression Regulation, Developmental* / physiology
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins / genetics*
  • Microtubule-Associated Proteins / metabolism
  • Microtubule-Associated Proteins / physiology*
  • Molecular Sequence Data
  • Pedigree
  • Up-Regulation / physiology


  • Microtubule-Associated Proteins
  • 1-Alkyl-2-acetylglycerophosphocholine Esterase
  • PAFAH1B1 protein, human