Human mutations in NDE1 cause extreme microcephaly with lissencephaly

Fowzan S. Alkuraya, Xuyu Cai, Carina Emery, Ganeshwaran H. Mochida, Mohammed S. Al-Dosari, Jillian M. Felie, R. Sean Hill, Brenda J. Barry, Jennifer N. Partlow, Generoso G. Gascon, Amal Kentab, Mohammad Jan, Ranad Shaheen, Yuanyi Feng*, Christopher A. Walsh

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

146 Scopus citations

Abstract

Genes disrupted in human microcephaly (meaning "small brain") define key regulators of neural progenitor proliferation and cell-fate specification. In comparison, genes mutated in human lissencephaly (lissos means smooth and cephalos means brain) highlight critical regulators of neuronal migration. Here, we report two families with extreme microcephaly and grossly simplified cortical gyral structure, a condition referred to as microlissencephaly, and show that they carry homozygous frameshift mutations in NDE1, which encodes a multidomain protein that localizes to the centrosome and mitotic spindle poles. Both human mutations in NDE1 truncate the C-terminal NDE1domains, which are essential for interactions with cytoplasmic dynein and thus for regulation of cytoskeletal dynamics in mitosis and for cell-cycle-dependent phosphorylation of NDE1 by Cdk1. We show that the patient NDE1 proteins are unstable, cannot bind cytoplasmic dynein, and do not localize properly to the centrosome. Additionally, we show that CDK1 phosphorylation at T246, which is within the C-terminal region disrupted by the mutations, is required for cell-cycle progression from the G2 to the M phase. The role of NDE1 in cell-cycle progression probably contributes to the profound neuronal proliferation defects evident in Nde1-null mice and patients with NDE1 mutations, demonstrating the essential role of NDE1 in human cerebral cortical neurogenesis.

Original languageEnglish (US)
Pages (from-to)536-547
Number of pages12
JournalAmerican journal of human genetics
Volume88
Issue number5
DOIs
StatePublished - May 13 2011

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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