ARX: a gene for all seasons

Gécz, Jozef; Cloosterman, Desiree; Partington, M. W.

doi:10.1016/j.gde.2006.04.003

Cited by 127 publications

(132 citation statements)

References 40 publications

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“…Other ARX mutations predicted to cause an early truncation of the ARX protein (EX2-5del, c.196+2T4C, c.232G4T; EX1-2.1del; reviewed in Ref. 4 ) have been described. Interestingly, virtually all of these cause the X-linked lissencephaly with ambiguous genitalia (XLAG) phenotype, which represents the severe malformation end of the phenotypic spectrum of ARX-associated disorders.…”

Section: Discussionmentioning

confidence: 99%

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Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

et al. 2009

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Aristaless-related homeobox (ARX) gene mutations cause a diverse spectrum of disorders of the human brain, including lissencephaly, various forms of epilepsy and non-syndromic mental retardation. We have identified a novel mutation, c.81C4G (p.Y27X), within the ARX gene in a family with two affected male cousins. One of the boys was diagnosed with an early infantile epileptic encephalopathy also known as Ohtahara syndrome, whereas his cousin had been diagnosed with West syndrome (WS). Both patients have normal genitalia and neither have lissencephaly. The ARX mutation identified is predicted to yield a severely truncated protein of only 26 amino acids and can be considered as a null mutation. Somewhat surprisingly, however, it does not yield the X-linked lissencephaly with ambiguous genitalia (XLAG) syndrome. We proposed that the ARX mRNA translation re-initiated at the next AUG codon at position c.121-123 (aa 41) and, thus, partly rescued these patients from XLAG. Our in vitro studies show that this N-terminally truncated ARX protein (p.M41_C562) is detected by western immunoblot in lysates from cells transiently transfected with an ARX over-expression construct containing the c.81C4G mutation. Although these findings widen the spectrum of clinical phenotypes because of mutations in the ARX gene, they also emphasize the molecular pathogenetic effect of individual mutations as well as the effect of genetic background resulting in intrafamilial clinical heterogeneity for these mutations.

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Section: Discussionmentioning

confidence: 99%

“…4 Limited human and extensive mouse gene-expression studies show high levels of ARX expression in the foetal brain as well as in some parts of the adult brain. In particular, ARX expression is high in the neuronal precursors of the germinal matrix and ventricular zones at all stages of development.…”

Section: Introductionmentioning

confidence: 99%

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

et al. 2009

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“…Mutations in the human ARX gene have been identified in a large variety of neuropathological conditions, including West and Partington syndromes, myoclonic epilepsy, lissencephaly, and nonsyndromic mental retardation (Kato et al, 2004;Gécz et al, 2006;Nawara et al, 2006). Both neuropathological studies in autoptic human tissues and analysis in Arx mutant animals provided evidence that Arx is necessary for the proper migration of subpallial neuronal progenitors to the cerebral cortex, and thus for the supply of the majority of GABAergic cortical interneurons (Bonneau et al, 2002;Kitamura et al, 2002;Colombo et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons

Colasante¹,

Collombat²,

Raimondi³

et al. 2008

J. Neurosci.

142

127

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The Arx transcription factor is expressed in the developing ventral telencephalon and subsets of its derivatives. Mutation of human ARX ortholog causes neurological disorders including epilepsy, lissencephaly, and mental retardation. We have isolated the mouse Arx endogenous enhancer modules that control its tightly compartmentalized forebrain expression. Interestingly, they are scattered downstream of its coding region and partially included within the introns of the downstream PolA1 gene. These enhancers are ultraconserved noncoding sequences that are highly conserved throughout the vertebrate phylum. Functional characterization of the Arx GABAergic enhancer element revealed its strict dependence on the activity of Dlx transcription factors. Dlx overexpression induces ectopic expression of endogenous Arx and its isolated enhancer, whereas loss of Dlx expression results in reduced Arx expression, suggesting that Arx is a key mediator of Dlx function. To further elucidate the mechanisms involved, a combination of gain-of-function studies in mutant Arx or Dlx tissues was pursued. This analysis provided evidence that, although Arx is necessary for the Dlx-dependent promotion of interneuron migration, it is not required for the GABAergic cell fate commitment mediated by Dlx factors. Although Arx has additional functions independent of the Dlx pathway, we have established a direct genetic relationship that controls critical steps in the development of telencephalic GABAergic neurons. These findings contribute elucidating the genetic hierarchy that likely underlies the etiology of a variety of human neurodevelopmental disorders.

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“…Subsequently, ARX mutations were shown to account for additional neurological conditions, including forms of nonsyndromic X-linked mental retardation, myoclonic epilepsy, Partington disease, and severe cases of lissencephaly associated with abnormal genitalia (XLAG) (Bienvenu et al, 2002;Kitamura et al, 2002;Stromme et al, 2002a;Poirier et al, 2006). Overall, the severity of the Arx mutation correlates with the clinical prognosis (Gecz et al, 2006). Dystonia is a condition that was frequently found in different ARX-dependent disorders.…”

Section: Introductionmentioning

confidence: 99%

Inactivation ofArx, the Murine Ortholog of the X-Linked Lissencephaly with Ambiguous Genitalia Gene, Leads to Severe Disorganization of the Ventral Telencephalon with Impaired Neuronal Migration and Differentiation

Colombo¹,

Collombat²,

Colasante³

et al. 2007

J. Neurosci.

129

134

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ARX loss-of-function mutations cause X-linked lissencephaly with ambiguous genitalia (XLAG), a severe neurological condition that results in profound brain malformations, including microcephaly, absence of corpus callosum, and impairment of the basal ganglia. Despite such dramatic defects, their nature and origin remain largely unknown. Here, we used Arx mutant mice as a model to characterize the cellular and molecular mechanisms underlying the basal ganglia alterations. In these animals, the early differentiation of this tissue appeared normal, whereas subsequent differentiation was impaired, leading to the periventricular accumulation of immature neurons in both the lateral ganglionic eminence and medial ganglionic eminence (MGE). Both tangential migration toward the cortex and striatum and radial migration to the globus pallidus and striatum were greatly reduced in the mutants, causing a periventricular accumulation of NPYϩ or calretininϩ neurons in the MGE. Arx mutant neurons retained their differentiation potential in vitro but exhibited deficits in morphology and migration ability. These findings imply that cell-autonomous defects in migration underlie the neuronal localization defects. Furthermore, Arx mutants lacked a large fraction of cholinergic neurons and displayed a strong impairment of thalamocortical projections, in which major axon fiber tracts failed to traverse the basal ganglia. Altogether, these results highlight the critical functions of Arx in promoting neural migration and regulating basal ganglia differentiation in mice, consistent with the phenotype of XLAG patients.

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ARX: a gene for all seasons

Cited by 127 publications

References 40 publications

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)

Arx Is a Direct Target of Dlx2 and Thereby Contributes to the Tangential Migration of GABAergic Interneurons

Inactivation ofArx, the Murine Ortholog of the X-Linked Lissencephaly with Ambiguous Genitalia Gene, Leads to Severe Disorganization of the Ventral Telencephalon with Impaired Neuronal Migration and Differentiation

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