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PLoS Genet. 2017 Apr 28;13(4):e1006746. doi: 10.1371/journal.pgen.1006746. eCollection 2017 Apr.

Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.

Author information

1
Institute of Cell Biology and Neurobiology, Charité University Medicine Berlin, Berlin, Germany.
2
Department of Pediatric Neurology, Charité University Medicine Berlin, Berlin, Germany.
3
Sozialpädiatrisches Zentrum (SPZ), Center for Chronic Sick Children, Charité University, Berlin, Germany.
4
Max Planck Institute for Molecular Genetics, Berlin, Germany.
5
Guangzhou Women and Children's Medical Center, Guangzhou, China.
6
Department of Molecular Genetics, University of Toronto, Toronto, Canada.
7
Program in Neurosciences & Mental Health, Hospital for Sick Children, Toronto, Canada.
8
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
9
Department of Pediatric Neurology, University Children's Hospital of Zurich, Zurich, Switzerland.
10
Department of Human Genetics, University of Würzburg, Würzburg, Germany.
11
Pediatrics, University Hospital, Technical University Dresden, Dresden, Germany.
12
Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

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.

PMID:
28453519
PMCID:
PMC5428974
DOI:
10.1371/journal.pgen.1006746
[Indexed for MEDLINE]
Free PMC Article

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