Expansions of polyAlanine repeats in ARX: Partial loss-of-function

Expansions of polyAlanine repeat tracts in the Aristaless-related homeobox (ARX) gene are responsible of a group of incurable X-linked neurodevelopmental disorders (NDDs) such as intellectual disabilities (XLID), chronic epilepsy, and infantile spasms. In patients, expanded runs of consecutive mixed (GCN)n repeats alter the first and the second polyAlanine tracts, from non-affected lengths of 12-16 to disease-associated lengths of 20-23 alanines. Our in vitro studies have proved that polyAlanine repeats are hypomorphic alterations causing a partial loss in ARX function, which acts as homeotic brain transcription factor. Expanded ARX proteins exhibit decreased transcriptional-activity and reduced DNA-binding to specific gene-regulatory regions.Ongoing efforts to define new strategy to identify useful tools towards drug discovery for ARX polyAlanine phenotypes.