Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.
PLoS Genet
; 13(4): e1006746, 2017 04.
Article
en En
| MEDLINE
| ID: mdl-28453519
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Movimiento Celular
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Mutación del Sistema de Lectura
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Factores de Intercambio de Guanina Nucleótido Rho
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Discapacidad Intelectual
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
PLoS Genet
Asunto de la revista:
GENETICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
Alemania