Increased dosage of the bifunctional transcription factor ARX disturbs its tuneable activity and may cause neuronal defects

Defective activity of dosage-sensitive transcription factors (TFs) has been established to change gene expression and cause a phenotypic effect during brain development. ARX is a bifunctional transcription factor capable of activating or repressing gene transcription, whose mutations have been found in a wide spectrum of neurodevelopmental disorders ranging from severe cortical malformations to mild Intellectual Disability (ID). Here, we report that ARX is a dosage-sensitive X-linked gene whose protein acts as a concentration-dependent TF in the regulation of direct and indirect disease targets. Our results demonstrate that not only a reduction but also an extra dosage of ARX may disturb the tuneable bifunctional activity and produce brain disorders.