Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival

Michael E. Coulter, Damir Musaev, Ellen M. DeGennaro, Xiaochang Zhang, Katrin Henke, Kiely N. James, Richard S. Smith, R. Sean Hill, Jennifer N. Partlow, Muna Al-Saffar, A. Stacy Kamumbu, Nicole Hatem, A. James Barkovich, Jacqueline Aziza, Nicolas Chassaing, Maha S. Zaki, Tipu Sultan, Lydie Burglen, Anna Rajab, Lihadh Al-GazaliGaneshwaran H. Mochida, Matthew P. Harris, Joseph G. Gleeson, Christopher A. Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Purpose: The exocyst complex is a conserved protein complex that mediates fusion of intracellular vesicles to the plasma membrane and is implicated in processes including cell polarity, cell migration, ciliogenesis, cytokinesis, autophagy, and fusion of secretory vesicles. The essential role of these genes in human genetic disorders, however, is unknown. Methods: We performed homozygosity mapping and exome sequencing of consanguineous families with recessively inherited brain development disorders. We modeled an EXOC7 splice variant in vitro and examined EXOC7 messenger RNA (mRNA) expression in developing mouse and human cortex. We modeled exoc7 loss-of-function in a zebrafish knockout. Results: We report variants in exocyst complex members, EXOC7 and EXOC8, in a novel disorder of cerebral cortex development. In EXOC7, we identified four independent partial loss-of-function (LOF) variants in a recessively inherited disorder characterized by brain atrophy, seizures, and developmental delay, and in severe cases, microcephaly and infantile death. In EXOC8, we found a homozygous truncating variant in a family with a similar clinical disorder. We modeled exoc7 deficiency in zebrafish and found the absence of exoc7 causes microcephaly. Conclusion: Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.

Original languageEnglish (US)
Pages (from-to)1040-1050
Number of pages11
JournalGenetics in Medicine
Volume22
Issue number6
DOIs
StatePublished - Jun 1 2020
Externally publishedYes

Keywords

  • EXOC7
  • EXOC8
  • developmental delay
  • exocyst
  • microcephaly

ASJC Scopus subject areas

  • Genetics(clinical)

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