LIS1 missense mutations. Variable phenotypes result from unpredictable alterations in biochemical and cellular properties

Michal Caspi, Frédéric M. Coquelle, Cynthia Koifman, Talia Levy, Hiroyuki Arai, Junken Aoki, Jan R. De Mey, Orly Reiner

Research output: Contribution to journalArticle

25 Citations (Scopus)

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 α1 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.

Original languageEnglish
Pages (from-to)38740-38748
Number of pages9
JournalJournal of Biological Chemistry
Volume278
Issue number40
DOIs
Publication statusPublished - 2003 Oct 3
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'LIS1 missense mutations. Variable phenotypes result from unpredictable alterations in biochemical and cellular properties'. Together they form a unique fingerprint.

Cite this