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  Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation

Ravindran, E., Hu, H., Yuzwa, S. A., Hernandez-Miranda, L. R., Kraemer, N., Ninnemann, O., et al. (2017). Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation. PLoS Genetics, 13(4): e1006746. doi:10.1371/journal.pgen.1006746.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0000-BF38-B Version Permalink: http://hdl.handle.net/21.11116/0000-0000-BF39-A
Genre: Journal Article

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 Creators:
Ravindran, E., Author
Hu, H., Author
Yuzwa, S. A., Author
Hernandez-Miranda, L. R., Author
Kraemer, N., Author
Ninnemann, O., Author
Musante, L., Author
Boltshauser, E., Author
Schindler, D., Author
Hübner, A., Author
Reinecker, H. C., Author
Ropers, H. H.1, Author              
Birchmeier, C., Author
Miller, F. D., Author
Wienker, T. F.2, Author              
Hübner, C., Author
Kaindl, A. M., Author
Affiliations:
1Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385695              
2Clinical Genetics (Thomas F. Wienker), Emeritus Group of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385696              

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Free keywords: Animals Cell Movement/*genetics Cytoskeleton/genetics Exome/genetics Female Frameshift Mutation/*genetics High-Throughput Nucleotide Sequencing Homozygote Humans Intellectual Disability/diagnostic imaging/*genetics/pathology Magnetic Resonance Imaging Male Mesencephalon/diagnostic imaging/pathology Mice Pedigree Rho Guanine Nucleotide Exchange Factors/*genetics Rhombencephalon/diagnostic imaging/pathology Signal Transduction rhoA GTP-Binding Protein/genetics
 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.

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Language(s): eng - English
 Dates: 2017-04-28
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1371/journal.pgen.1006746
ISSN: 1553-7404 (Electronic)
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Title: PLoS Genetics
  Other : PLoS Genet.
Source Genre: Journal
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Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 13 (4) Sequence Number: e1006746 Start / End Page: - Identifier: ISSN: 1553-7390
CoNE: https://pure.mpg.de/cone/journals/resource/1000000000017180