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Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation

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Item Type:Article
Title:Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation
Creators Name:Ravindran, E. and Hu, H. and Yuzwa, S.A. and Hernandez-Miranda, L.R. and Kraemer, N. and Ninnemann, O. and Musante, L. and Boltshauser, E. and Schindler, D. and Hübner, A. and Reinecker, H.-C. and Ropers, H.-H. and Birchmeier, C. and Miller, F.D. and Wienker, T.F. and Hübner, C. and Kaindl, A.M.
Abstract:Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.
Keywords:Cell Movement, Cytoskeleton, Exome, Frameshift Mutation, High-Throughput Nucleotide Sequencing, Homozygote, Intellectual Disability, Magnetic Resonance Imaging, Mesencephalon, Pedigree, Rho Guanine Nucleotide Exchange Factors, Rhombencephalon, Signal Transduction, rhoA GTP-Binding Protein, Animals, Mice
Source:PLoS Genetics
ISSN:1553-7404
Publisher:Public Library of Science (U.S.A.)
Volume:13
Number:4
Page Range:e1006746
Date:28 April 2017
Official Publication:https://doi.org/10.1371/journal.pgen.1006746
PubMed:View item in PubMed

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