Aristaless-related homeobox gene disruption leads to abnormal distribution of GABAergic interneurons in human neocortex: evidence based on a case of X-linked lissencephaly with abnormal genitalia (XLAG)

Abstract

X-linked lissencephaly with abnormal genitalia (XLAG) is a rare disorder caused by mutations in the aristaless-related homeobox (ARX) gene, located on Xp22.13. Arx-null mice show loss of tangential migration of GABAergic interneurons, presumably being related to caudal ganglionic eminence tangential migration. In the present study, we investigated a subpopulation of GABAergic interneurons in the brain of an infant with XLAG, who had a novel nonsense mutation of the ARX gene, compared with those of age-matched normal controls and Miller-Dieker syndrome. We performed immunocytochemistry for interneuron and migration markers. We found that glutamic acid decarboxylase (GAD)- and calretinin (CR)-containing cells were significantly reduced in the neocortex and located in the white matter and neocortical subventricular zone, while neuropeptide Y- or cholecystokinin-containing cells were normally distributed. Moreover, in the neocortical subventricular region, the GAD- and CR-containing cells expressed the radial migration marker Mash-1 as well as nestin. Our findings suggest that ARX protein controls not only the tangential migration of GABAergic interneurons from the ganglionic eminence, but also may serve to induce radial migration from the neocortical subventricular zone.

Genetics and mechanisms leading to human cortical malformations

“…Neuropathological reports for XLAG syndrome are rare [54,[126][127][128]. In all reported cases, the cortical ribbon is of intermediate thickness (less than 10 mm) and the corpus callosum is absent.…”

Neuronal migration disorders: clinical, neuroradiologic and genetics aspects

“…ARX's role in nervous system development is confirmed by numerous syndromes genetically related: X-linked infantile spasms (West syndrome), X-linked myoclonic epilepsy with spasticity and mental retardation, X-linked mental retardation, Partington syndrome (mental retardation, dystonic movements of the hands and dysarthria), Proud syndrome (acquired microcephaly, mental retardation, agenesis of the corpus callosum and peculiar facies), hydranencephaly with ambiguous genitalia, XLAG syndrome. XLAG is a syndrome described in 1999, presenting with lissencephaly (more severe than LIS1 or DCX-related lissencephaly), agenesis of the corpus callosum, refractory epilepsy (with tonic, multifocal myoclonic or generalized tonic-clonic seizures) of neonatal onset, acquired microcephaly and male genotype with ambiguous genitalia; all patients show intractable epilepsy and lacked psychomotor development, and the most of cases die before the age of 18 months (33).…”

Neurons on the Move: Migration and Lamination of Cortical Interneurons

“…Human mutations in the transcription factor Arx , which is necessary for the Dlx-dependent promotion of interneuron migration, are associated with neurological disorders including lissencephaly, mental retardation and epilepsy (X-linked lissencephaly associated with abnormal genitalia, XLAG syndrome). These conditions display aberrant migration and differentiation of interneurons [220], and many of the neurological phenotypes observed in patients can be attributed to interneuron dysfunction. …”