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. Author summary During brain
development, localized gene expression is crucial for the formation and
function of specific brain regions. Various groups of proteins are known to
regulate segmentation through controlled gene expression, among them, the Rho
GTPase regulator family. In this study, we identified a frameshift mutation in
the Rho guanine nucleotide exchange factor 2 gene (ARHGEF2) in two children
presenting with intellectual disability, mild microcephaly, and a midbrain-
hindbrain malformation. This phenotype is also observed in Arhgef2 mutant
mice, highlighting the importance of ARHGEF2 across development of distinct
mammalian species. We show that loss of Arhgef2 affects neurogenesis and also
cell migration. In addition, we extended the current knowledge of ARHGEF2
expression and its role in early central nervous system development, with
special reference to the formation of the precerebellar system. In addition to
extensive literature on ARHGEF2, we now provide evidence for its significant
role in neuronal migration in brain development and link the gene to human
neurodevelopmental disease
