Mutations in ARX result in several defects involving GABAergic neurons

Friocourt Friocourt

doi:10.3389/fncel.2010.00004

Abstract

Genetic investigations of X-linked mental retardation have demonstrated the implication of ARX in a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities, but with associated features of dystonia and epilepsy. These investigations have in recent years directed attention to the role of this gene in brain development. Analysis of its spatio-temporal localization profile revealed expression in telencephalic structures at all stages of development, mainly restricted to populations of GABA-containing neurons. Furthermore, studies of the effects of ARX loss of function either in humans or in lines of mutant mice revealed varying defects, suggesting multiple roles of this gene during development. In particular, Arx has been shown to contribute to almost all fundamental processes of brain development: patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. In this review, we will present and discuss recent findings concerning the role of ARX in brain development and how this information will be useful to better understand the pathophysiological mechanisms of mental retardation and epilepsy associated with ARX mutations.

Highlights

In the last years, defects in transcription regulation have been linked to several monogenic neurodevelopmental disorders resulting, in some cases, in cerebral malformations, mental retardation and/or autism
Such defects may result from mutations located directly in genes encoding transcription factors such as ZIC2 (Zinc finger protein of the cerebellum 2), responsible for holoprosencephaly (Brown et al, 1998). As these transcription factors often have precise spatio-temporal expression profiles as well as multiple trans-acting co-factors, mutations in these genes can have pleiotropic effects. This is, for example, the case for ARX, which has been shown in humans to be responsible for a wide spectrum of brain disorders ranging from phenotypes with severe neuronal migration defects, such as lissencephaly, to milder forms of X-linked mental retardation (XLMR) often associated with epilepsy, but without apparent brain abnormalities
Which represents the other end of the spectrum of brain disorders associated with ARX mutations, is a heterogeneous group of cortical malformations resulting from mutations in at least five different genes: LIS1, DCX, RELN, ARX and TUBA1A (Reiner et al, 1993; des Portes et al, 1998; Gleeson et al, 1998; Hong et al, 2000; Kitamura et al, 2002; Keays et al, 2007)