ZFIN ID: ZDB-PUB-200229-4
Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
Coulter, M.E., Musaev, D., DeGennaro, E.M., Zhang, X., Henke, K., James, K.N., Smith, R.S., Hill, R.S., Partlow, J.N., Muna Al-Saffar, ., Kamumbu, A.S., Hatem, N., Barkovich, A.J., Aziza, J., Chassaing, N., Zaki, M.S., Sultan, T., Burglen, L., Rajab, A., Al-Gazali, L., Mochida, G.H., Harris, M.P., Gleeson, J.G., Walsh, C.A.
Date: 2020
Source: Genetics in medicine : official journal of the American College of Medical Genetics   22(6): 1040-1050 (Journal)
Registered Authors: Harris, Matthew, Henke, Katrin
Keywords: EXOC7, EXOC8, developmental delay, exocyst, microcephaly
MeSH Terms:
  • Animals
  • Brain Diseases*
  • Cell Proliferation/genetics
  • Homozygote
  • Humans
  • Mice
  • Microcephaly*/genetics
  • Zebrafish/genetics
PubMed: 32103185 Full text @ Genet. Med.
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ABSTRACT
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.
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.
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.
Our results highlight the essential role of the exocyst pathway in normal cortical development and how its perturbation causes complex brain disorders.
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