Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
| Autor: | Richard S. Smith, Kiely N. James, Ganeshwaran H. Mochida, Matthew P. Harris, R. Sean Hill, Xiaochang Zhang, Christopher A. Walsh, Lihadh Al-Gazali, Lydie Burglen, Nicole E. Hatem, Tipu Sultan, Michael E. Coulter, Ellen M DeGennaro, Anna Rajab, Muna Al-Saffar, A. Stacy Kamumbu, Katrin Henke, Jacqueline Aziza, A. James Barkovich, Jennifer N. Partlow, Damir Musaev, Nicolas Chassaing, Joseph G. Gleeson, Maha S. Zaki |
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| Rok vydání: | 2020 |
| Předmět: |
Microcephaly
EXOC7 Intellectual and Developmental Disabilities (IDD) 1.1 Normal biological development and functioning Clinical Sciences Exocyst Biology EXOC8 Neurodegenerative Article Mice Rare Diseases Clinical Research Underpinning research Ciliogenesis medicine Genetics Animals Humans 2.1 Biological and endogenous factors microcephaly Aetiology Intellectual and Developmental Disabilities Zebrafish Genetics (clinical) Cell Proliferation Pediatric Genetics & Heredity Brain Diseases Homozygote Neurosciences Disease gene identification medicine.disease biology.organism_classification Cell biology Brain Disorders developmental delay medicine.anatomical_structure exocyst Mental Health Cerebral cortex Neurological Congenital Structural Anomalies Cytokinesis |
| Zdroj: | Genetics in medicine : official journal of the American College of Medical Genetics, vol 22, iss 6 Genetics in Medicine |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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