TY - JOUR
T1 - Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival
AU - Coulter, Michael E.
AU - Musaev, Damir
AU - DeGennaro, Ellen M.
AU - Zhang, Xiaochang
AU - Henke, Katrin
AU - James, Kiely N.
AU - Smith, Richard S.
AU - Hill, R. Sean
AU - Partlow, Jennifer N.
AU - Al-Saffar, Muna
AU - Kamumbu, A. Stacy
AU - Hatem, Nicole
AU - Barkovich, A. James
AU - Aziza, Jacqueline
AU - Chassaing, Nicolas
AU - Zaki, Maha S.
AU - Sultan, Tipu
AU - Burglen, Lydie
AU - Rajab, Anna
AU - Al Gazali, Lihadh Ibrahim
AU - Mochida, Ganeshwaran H.
AU - Harris, Matthew P.
AU - Gleeson, Joseph G.
AU - Walsh, Christopher A.
N1 - Publisher Copyright:
© 2020, The Author(s).
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
KW - EXOC7
KW - EXOC8
KW - developmental delay
KW - exocyst
KW - microcephaly
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U2 - 10.1038/s41436-020-0758-9
DO - 10.1038/s41436-020-0758-9
M3 - Article
C2 - 32103185
AN - SCOPUS:85080082434
SN - 1098-3600
VL - 22
SP - 1040
EP - 1050
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 6
ER -