Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation

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.中后脑畸形可在胚胎发生过程中，因这些特异性脑结构内短暂且局部的基因表达模式紊乱而诱发。Rho鸟苷酸交换因子（Rho guanine nucleotide exchange factor，ARHGEF）家族成员是调控Rho GTPase时空激活的关键蛋白，可调节细胞骨架动力学、细胞分裂与细胞迁移过程。我们通过全外显子测序（whole exome sequencing），在一个库尔德-土耳其血统的近亲婚配家系中，鉴定出ARHGEF2基因的纯合移码突变，该突变可导致智力障碍、中后脑畸形与轻度小头畸形。研究表明，ARHGEF2功能缺失会扰乱祖细胞分化，该现象与有丝分裂纺锤体平面取向改变相关，推测该改变更易促进对称分裂。该ARHGEF2突变会降低调控细胞迁移的关键通路——RhoA/ROCK/MLC信号通路的激活水平。我们证实，ARHGEF2突变小鼠可重现人类脑畸形表型，并明确小脑前体系统的不同组分出现异常迁移，这是中后脑表型的潜在致病机制。本研究凸显了ARHGEF2在人类脑发育中的关键功能，并将ARHGEF2突变鉴定为一种新型神经发育障碍的致病原因。