Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy

Abstract

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation. At least eight autosomal genes involved in idiopathic epilepsy have been identified, and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome-linked, Aristaless-related, homeobox gene (ARX), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine and polyglutamine disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.

The homeobox gene Arx is a novel positive regulator of embryonic myogenesis

“…Although Arx contains a homeobox DNA-binding domain, 23 it is currently unknown whether its interaction with the Myogenin promoter is direct, mediated or stabilized by other factors. Moreover, as Arx appears to interact physically with Mef2C, but not directly with MyoD, the ability shown by Arx to activate to a certain extent the Myogenin promoter in CH310T1/2 in absence of exogenous Mef2C suggests that Mef2C may be induced by MyoD 24 or that other factors participate in the activation.…”

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

“…Major advances in the elucidation of the monogenic causes of mental retardation and epilepsy has been achieved recently, in particular for forms of X-chromosome linked mental retardation (or XLMR) and idiopathic epilepsy (for review, see Chelly and Mandel, 2001;Mulley et al, 2003). Among others, a specific form of X-chromosome linked West syndrome (early onset, severe infantile epilepsy, also called X-linked infantile spasms syndrome or ISSX; mapped to Xp22) has been shown to result from the ARX gene mutations (Strømme et al, 2002a). The ARX gene is a novel paired-type, highly conserved homeobox gene with orthologs in birds (Gallus gallus; V. Broccoli, unpublished data), amphibians (Xenopus laevis; El-Hodiri et al, 2003), and flies (Drosophila melanogaster), where it was named aristaless (Campbell and Tomlinson, 1998).…”

“…Among others, polyalanine tract expansion mutations have been detected. One of them, the dup24bp mutation (Strømme et al, 2002a), is so far the most frequent mutation causing nonsyndromic mental retardation and shows the widest range of clinical presentations (Strømme et al, 2002b). Although the pathogenic role of the expanded polyalanine tracts is not deciphered yet, it is unlikely that they would cause protein aggregation seen in the other dominant disorders due to polyalanine and polyglutamine expansions.…”

Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome

“…Polyalanine expansion mutations involving homeodomain or non-homeodomain transcription factors (HOXA13, HOXD13, ARX, RUNX2, ZIC2, FOXL2) have been described in several human malformations 10,11 . In each of these cases, both the normal and expanded alanine tracts range in a similar size, suggesting a common underlying mechanism.…”