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
AU - Mochida, Ganeshwaran H.
AU - Harris, Matthew P.
AU - Gleeson, Joseph G.
AU - Walsh, Christopher A.
N1 - Funding Information:
We thank the families for their invaluable participation in our study. M.E.C. was supported by F30 MH102909, Howard Hughes Medical Institute Medical Student Fellowship, and Nancy Lurie Marks Family Foundation Medical Student Fellowship. C.A.W.
Funding Information:
was supported by R01 NS35129 and R01NS032457 from the National Institute of Neurological Disorders and Stroke (NINDS), U01MH106883 from the National Institute of Mental Health (NIMH), and the Allen Discovery Center program through The Paul G. Allen Frontiers Group. C.A.W. and J.G.G. are Investigators of the Howard Hughes Medical Institute. X.Z. was supported by K01MH109747 from the NIMH. K.H. and M.P.H. were supported in part through funding from Children’s Hospital Orthopaedic Surgery Foundation. This work was also supported by the Broad Center for Mendelian Genomics (UM1 HG008900) funded by the National Human Genome Research Institute (NHGRI). E.M.D. was supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB) under award 5T32EB1680. R.S.S. was supported by NINDS (F32NS100033801, K99NS112604). J.A., N. C., and L.B. were supported by the French Health Ministry (PNMR2-PNMR3).
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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UR - http://www.scopus.com/inward/citedby.url?scp=85080082434&partnerID=8YFLogxK
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 -