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

Genet Med. 2020 Jun;22(6):1040-1050. doi: 10.1038/s41436-020-0758-9.

Michael E Coulter ¹ ², Damir Musaev ³, Ellen M DeGennaro ¹ ⁴, Xiaochang Zhang ¹ ⁵, Katrin Henke ⁶, Kiely N James ³, Richard S Smith ¹, R Sean Hill ¹, Jennifer N Partlow ¹, Muna Al-Saffar ¹ ⁷, A Stacy Kamumbu ¹, Nicole Hatem ¹, A James Barkovich ⁸, Jacqueline Aziza ⁹, Nicolas Chassaing ¹⁰ ¹¹, Maha S Zaki ¹², Tipu Sultan ¹³, Lydie Burglen ¹⁴ ¹⁵, Anna Rajab ¹⁶, Lihadh Al-Gazali ⁷, Ganeshwaran H Mochida ¹ ¹⁷, Matthew P Harris ⁶, Joseph G Gleeson ¹⁸, Christopher A Walsh ¹⁹

Affiliations

1 Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA.
2 Program in Neuroscience and Harvard/MIT MD-PHD Program, Harvard Medical School, Boston, MA, USA.
3 Department of Neurosciences and Howard Hughes Medical Institute, University of San Diego, La Jolla, CA, USA.
4 Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
5 Department of Human Genetics, University of Chicago, Chicago, IL, USA.
6 Division of Orthopedic Research, Boston Children's Hospital, Department of Genetics, Harvard Medical School, Boston, MA, USA.
7 Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.
8 Benioff Children's Hospital, Departments of Radiology, Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
9 Département de Pathologie, Institut Universitaire du Cancer de Toulouse-Oncopole-CHU Toulouse, Toulouse, France.
10 Service de Génétique Médicale, CHU Toulouse, Toulouse, France.
11 UDEAR; UMR 1056 Inserm-Université de Toulouse, Toulouse, France.
12 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
13 Department of Pediatric Neurology, Institute of Child Health & The Children's Hospital, Lahore, Pakistan.
14 Centre de référence des malformations et maladies congénitales du cervelet, Département de génétique, AP-HP.Sorbonne Université, Paris, France.
15 Hôpital Trousseau and Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163, Paris, France.
16 National Genetics Center, Directorate General of Health Affairs, Ministry of Health, Muscat, Oman.
17 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
18 Department of Neurosciences and Howard Hughes Medical Institute, University of San Diego, La Jolla, CA, USA. jogleeson@ucsd.edu.
19 Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children's Hospital, Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. christopher.walsh@childrens.harvard.edu.

PMID: 32103185 DOI: 10.1038/s41436-020-0758-9

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.

Keywords

EXOC7; EXOC8; developmental delay; exocyst; microcephaly.

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