RESUMEN
The relationships between impaired cortical development and consequent malformations in neurodevelopmental disorders, as well as the genes implicated in these processes, are not fully elucidated to date. In this study, we report six novel cases of patients affected by BBSOAS (Boonstra-Bosch-Schaff optic atrophy syndrome), a newly emerging rare neurodevelopmental disorder, caused by loss-of-function mutations of the transcriptional regulator NR2F1. Young patients with NR2F1 haploinsufficiency display mild to moderate intellectual disability and show reproducible polymicrogyria-like brain malformations in the parietal and occipital cortex. Using a recently established BBSOAS mouse model, we found that Nr2f1 regionally controls long-term self-renewal of neural progenitor cells via modulation of cell cycle genes and key cortical development master genes, such as Pax6. In the human fetal cortex, distinct NR2F1 expression levels encompass gyri and sulci and correlate with local degrees of neurogenic activity. In addition, reduced NR2F1 levels in cerebral organoids affect neurogenesis and PAX6 expression. We propose NR2F1 as an area-specific regulator of mouse and human brain morphology and a novel causative gene of abnormal gyrification.
Asunto(s)
Factor de Transcripción COUP I/metabolismo , Neocórtex/embriología , Células-Madre Neurales/metabolismo , Lóbulo Occipital/embriología , Atrofias Ópticas Hereditarias/embriología , Lóbulo Parietal/embriología , Animales , Factor de Transcripción COUP I/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Neocórtex/patología , Células-Madre Neurales/patología , Lóbulo Occipital/patología , Atrofias Ópticas Hereditarias/genética , Atrofias Ópticas Hereditarias/patología , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/metabolismo , Lóbulo Parietal/patologíaRESUMEN
LHON has been suggested to involve both mitochondrial and X-chromosome-linked loci. By extending two-locus mitochondrial and nuclear gene analytic methods, we recently proposed that a proportion of affected females are likely heterozygous at the X-linked locus and affected due to unfortunate X-chromosome inactivation. Assuming that the optic tissue is the primary site of action of the mutant gene(s), we further propose here that there should be no fewer than six embryonic precursor cells for the involved optic tissue at the stage in early development when X-chromosome inactivation occurs. We also estimate that the disease threshold (i.e. proportion of cells with abnormal X-chromosome active in the responsible tissue at the time of X-chromosome inactivation) for a heterozygous female is in the range of 0.60 to 0.83.