Human mutations in NDE1 cause extreme microcephaly with lissencephaly [corrected]
Fowzan S Alkuraya1, Xuyu Cai, Carina Emery
1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
American Journal of Human Genetics
|May 3, 2011
Summary
Mutations in the NDE1 gene cause microlissencephaly, a severe brain development disorder. These NDE1 mutations disrupt cell division and neuronal proliferation, highlighting NDE1's crucial role in brain development.
Area of Science:
- Genetics
- Neuroscience
- Developmental Biology
Background:
- Microcephaly and lissencephaly are brain development disorders linked to specific gene disruptions.
- Genes in microcephaly regulate neural progenitor proliferation, while lissencephaly genes control neuronal migration.
Purpose of the Study:
- Investigate the genetic cause of microlissencephaly, a severe brain malformation.
- Identify the role of the NDE1 gene in human cerebral cortical neurogenesis.
Main Methods:
- Genetic analysis of two families with microlissencephaly.
- Characterization of NDE1 mutations and their impact on protein function.
- Analysis of NDE1 protein stability, dynein binding, and cell-cycle regulation.
Main Results:
- Identified homozygous frameshift mutations in NDE1 in patients with microlissencephaly.
- Mutations truncate NDE1, affecting cytoplasmic dynein interaction and centrosome localization.
- NDE1 phosphorylation by CDK1 at T246 is essential for G2 to M phase cell-cycle progression.
Conclusions:
- NDE1 is essential for human cerebral cortical neurogenesis.
- NDE1 mutations lead to severe neuronal proliferation defects and microlissencephaly.
- Proper NDE1 function is critical for regulating cytoskeletal dynamics and cell-cycle progression during brain development.
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