Described disorders caused by mutations in the ARX gene include: hydrocephaly with abnormal genitalia (HYD-AG), lissencephaly with abnormal genitalia (XLAG), agenesis of corpus callosum with abnormal genitalia (ACC-AG), Partington syndrome (PRTS), X-linked infantile spasms (ISSX), myoclonic epilepsy with spasticity and mental retardation (XMESID), and nonspecific mental retardation (NS-XLMR).
We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG)(7)'expansion' of pA1 and c.429_452dup 'dup24bp' of pA2).
We review the reported phenotypes of females with mutations in ARX and highlight the importance of screening ARX in male and female patients with ID, seizures, and in particular with complete ACC.
Mutations in the Aristaless-related homeobox (ARX) gene are associated with pleiotropic phenotypes including infantile spasms, mental retardation and dystonia.
Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms.
Mutations in the Aristaless Related Homeobox (ARX) gene are associated with a spectrum of structural (lissencephaly) and functional (epilepsy and intellectual disabilities) neurodevelopmental disorders.
Mouse orthologue of ARX, a gene mutated in several X-linked forms of mental retardation and epilepsy, is a marker of adult neural stem cells and forebrain GABAergic neurons.
Our data suggest expansions in one of the ARX polyA tracts results in nuclear protein aggregation and an increase in cell death; likely underlying the pathogenesis of the associated infantile spasms and mental retardation.
Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8.
Our data suggest expansions in one of the ARX polyA tracts results in nuclear protein aggregation and an increase in cell death; likely underlying the pathogenesis of the associated infantile spasms and mental retardation.
The Aristaless-related homeobox gene (ARX) is one of the most frequently mutated genes in a spectrum of X-chromosome phenotypes with intellectual disability (ID) as their cardinal feature.