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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.
