1. Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
- Author
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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, and Walsh, Christopher A
- Subjects
Genetics ,Pediatric ,Brain Disorders ,Congenital Structural Anomalies ,Rare Diseases ,Mental Health ,Neurodegenerative ,Neurosciences ,Clinical Research ,Intellectual and Developmental Disabilities (IDD) ,1.1 Normal biological development and functioning ,2.1 Biological and endogenous factors ,Aetiology ,Underpinning research ,Neurological ,Animals ,Brain Diseases ,Cell Proliferation ,Homozygote ,Humans ,Mice ,Microcephaly ,Zebrafish ,exocyst ,EXOC7 ,EXOC8 ,microcephaly ,developmental delay ,Clinical Sciences ,Genetics & Heredity - Abstract
PurposeThe 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.MethodsWe 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.ResultsWe 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.ConclusionOur results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
- Published
- 2020