Neurodevelopmental mutation of giant ankyrin-G disrupts a core mechanism for axon initial segment assembly

Rui Yang, Kathryn K. Walder-Christensen, Samir Lalani, Haidun Yan, Irene Díez García-Prieto, Sara Álvarez, Alberto Fernández-Jaén, Laura Speltz, Yong Hui Jiang, Vann Bennett

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Giant ankyrin-G (gAnkG) coordinates assembly of axon initial segments (AISs), which are sites of action potential generation located in proximal axons of most vertebrate neurons. Here, we identify a mechanism required for normal neural development in humans that ensures ordered recruitment of gAnkG and β4-spectrin to the AIS. We identified 3 human neurodevelopmental missense mutations located in the neurospecific domain of gAnkG that prevent recruitment of β4-spectrin, resulting in a lower density and more elongated pattern for gAnkG and its partners than in the mature AIS. We found that these mutations inhibit transition of gAnkG from a closed configuration with close apposition of Nand C-terminal domains to an extended state that is required for binding and recruitment of β4-spectrin, and normally occurs early in development of the AIS. We further found that the neurospecific domain is highly phosphorylated in mouse brain, and that phosphorylation at 2 sites (S1982 and S2619) is required for the conformational change and for recruitment of β4-spectrin. Together, these findings resolve a discrete intermediate stage in formation of the AIS that is regulated through phosphorylation of the neurospecific domain of gAnkG.

Original languageEnglish (US)
Pages (from-to)19717-19726
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number39
StatePublished - Sep 24 2019


  • Axon initial segment
  • Giant ankyrin-G
  • Neurodevelopmental mutation
  • Phosphorylation
  • β-4 spectrin

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