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

• Published in: Genetics in medicine Vol. 22; no. 6; pp. 1040 - 1050
• Main Authors: Coulter, Michael E., Musaev, Damir, DeGennaro, Ellen M., Zhang, Xiaochang, Henke, Katrin, James, Kiely N., Smith, Richard S., Hill, R. Sean, Partlow, Jennifer N., Muna Al-Saffar, Kamumbu, A. Stacy, Hatem, Nicole, Barkovich, A. James, Aziza, Jacqueline, Chassaing, Nicolas, Zaki, Maha S., Sultan, Tipu, Burglen, Lydie, Rajab, Anna, Al-Gazali, Lihadh, Mochida, Ganeshwaran H., Harris, Matthew P., Gleeson, Joseph G., Walsh, Christopher A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.06.2020; Elsevier Limited
• Subjects: Animals; Atrophy; Autophagy; Biomedical and Life Sciences; Biomedicine; Brain Diseases; Brain research; Cell adhesion & migration; Cell cycle; Cell division; Cell growth; Cell Proliferation - genetics; CRISPR; Experiments; Genetics; Genomes; Genomics; Health sciences; Homozygote; Hospitals; Human Genetics; Humans; Laboratory Medicine; Medicine; Mice; Microcephaly; Microcephaly - genetics; Mutagenesis; Neurology; Pediatrics; Zebrafish; Zebrafish - genetics; microcephaly; developmental delay; exocyst; EXOC8; EXOC7
• ISSN: 1098-3600; 1530-0366
• DOI: 10.1038/s41436-020-0758-9

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.