Neurodevelopmental disorders linked to Aristaless homeobox gene: A 'fault disease model'

Studying molecular convergence in neurodevelopmental disorders caused by mutations in specific disease-related genes permits us to define druggable molecular pathways. The purpose of our study is to assess the degree of damage associated with the ARX-KDM5C and to establish a correlation between similar phenotypes and same cellular functions. Mutations in Aristaless-related homeobox gene (ARX), a homeotic transcription factor with a key role in interneuron maturation, have been found in a spectrum of X-chromosome phenotypes including cortical malformations, chronic Epilepsy and X-Linked Intellectual Disabilities (XLID). About Lysine-specific demethylase 5C (KDM5C), its mutations have been reported as an important cause of XLID. Its protein is a histone demethylase acting as transcriptional repressor during brain development. Here we summarize functional analysis of two classes of ARX mutations : 1. PolyAlanine elongations affecting the first and the second PolyA tracts, frequently found in patients with Epilepsy or XLID; and 2. Missense mutations clustered in the paired-type homeodomain (HD) found in patients with Lissencephaly with abnormal genitalia (XLAG). Thus, we propose a "fault disease model" showing that the degree of spectrum of defects in transcription of ARX-target genes correlate with the severity of the neurophenotypes associated with ARX mutations.