Title | Regulation of human cerebral cortical development by EXOC7 and EXOC8, components of the exocyst complex, and roles in neural progenitor cell proliferation and survival. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Coulter, ME, Musaev, D, DeGennaro, EM, Zhang, X, Henke, K, James, KN, Smith, RS, R Hill, S, Partlow, JN, A Kamumbu, S, Hatem, N, A Barkovich, J, Aziza, J, Chassaing, N, Zaki, MAHS, Sultan, T, Burglen, L, Rajab, A, Al-Gazali, L, Mochida, GH, Harris, MP, Gleeson, JG, Walsh, CA |
Journal | Genet Med |
Volume | 22 |
Issue | 6 |
Pagination | 1040-1050 |
Date Published | 2020 06 |
ISSN | 1530-0366 |
Keywords | Animals, Brain Diseases, Cell Proliferation, Homozygote, Humans, Mice, Microcephaly, Zebrafish |
Abstract | 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. |
DOI | 10.1038/s41436-020-0758-9 |
Alternate Journal | Genet Med |
PubMed ID | 32103185 |
PubMed Central ID | PMC7272323 |
Grant List | UM1 HG008900 / HG / NHGRI NIH HHS / United States F32 NS100338 / NS / NINDS NIH HHS / United States T32 EB001680 / EB / NIBIB NIH HHS / United States / HH / Howard Hughes Medical Institute / United States 5T32EB1680 / EB / NIBIB NIH HHS / United States R01 NS035129 / NS / NINDS NIH HHS / United States F30 MH102909 / MH / NIMH NIH HHS / United States K99 NS112604 / NS / NINDS NIH HHS / United States K01 MH109747 / MH / NIMH NIH HHS / United States R01 NS032457 / NS / NINDS NIH HHS / United States R01 NS35129 / NS / NINDS NIH HHS / United States U01 MH106883 / MH / NIMH NIH HHS / United States Medical Student Fellowship / HH / Howard Hughes Medical Institute / United States |