ArticlePLoS genetics2017
Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.
Article in PLoS genetics, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 30 citations in OpenAlex.
- Prenatal and postnatal effects of gestational immune activation on synaptic and neurodevelopmental pathways via epigenetic mechanisms.Translational psychiatry · 2026Article
- Genetic architecture of childhood speech disorder: a review.Molecular psychiatry · 2024Review
- Non-coding de novo mutations in chromatin interactions are implicated in autism spectrum disorder.Molecular psychiatry · 2022Article
- Homozygous mutation inJournal of medical genetics · 2022Article
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- Case report: Expanding the phenotype ofFrontiers in neurology · 2022Article
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- Expanding the phenotype of NUP85 mutations beyond nephrotic syndrome to primary autosomal recessive microcephaly and Seckel syndrome spectrum disorders.Human molecular genetics · 2021Article
- Arhgef2 regulates mitotic spindle orientation in hematopoietic stem cells and is essential for productive hematopoiesis.Blood advances · 2021Article
- An ancestral recombination graph of human, Neanderthal, and Denisovan genomes.Science advances · 2021Article
- Article
- Neuronal Cytoskeleton in Intellectual Disability: From Systems Biology and Modeling to Therapeutic Opportunities.International journal of molecular sciences · 2021Review
- Pontocerebellar Hypoplasia: a Pattern Recognition Approach.Cerebellum (London, England) · 2020Article
- Mutated RAP1GDS1 causes a new syndrome of dysmorphic feature, intellectual disability & speech delay.Annals of clinical and translational neurology · 2020Article
- A chromosome 1q22 microdeletion includingMolecular cytogenetics · 2020Article
- Regulators of Rho GTPases in the Nervous System: Molecular Implication in Axon Guidance and Neurological Disorders.International journal of molecular sciences · 2019Review
- Emerging RAS superfamily conditions involving GTPase function.PLoS genetics · 2019Article
- MACF1 Mutations Encoding Highly Conserved Zinc-Binding Residues of the GAR Domain Cause Defects in Neuronal Migration and Axon Guidance.American journal of human genetics · 2018Article
- Review: Synthetic scaffolds to control the biochemical, mechanical, and geometrical environment of stem cell-derived brain organoids.APL bioengineering · 2018Review
- Rho GTPases in Intellectual Disability: From Genetics to Therapeutic Opportunities.International journal of molecular sciences · 2018Review
Corrections and comments
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Authors and funding
17 authors at 9 institutions in 5 countries.
Funding
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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Registered trials
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