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Our mutational analysis did not show any dup(24pb) in our patients. This work aimed to study c.428–451dup (24 bp) mutation in the exon 2 of the ARX gene in 118 males’ Moroccan patients with milder NS-ID to evaluate if the gene screening is a good tool for identifying NS-ID. Epidemiological and genetic studies about ID in the Moroccan population remain very scarce, and none study is carried out on the ARX gene. The most recurrent mutation of this gene is a duplication of 24pb, c.428-451dup. Mutations in the Aristaless Related Homeobox gene ( ARX ) have been identified to cause syndromic and nonsyndromic (NS-ID). Intellectual Disability (ID) represents a neuropsychiatric disorder, which its etiopathogenesis remains insufficiently understood. The identification of these effects can aid in the design of pathway-guided therapy for ARX-endophenotypes and NDDs with overlapping comorbidities. Overall, our data reveal alterations mirroring the overlapping and variant effects caused by null and polyalanine expanded mutations in ARX. Consistent with a conserved role of ARX in modulating AS, we propose that the allelic-dependent secondary synaptopathy results from aberrant Neurexin-1 repertoire.
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Abnormal AS repertoires in Neurexin-1, a gene encoding multiple pre-synaptic organizers implicated in synaptic remodelling, were detected in Arx/alr-1(KO) animals and in Arx(GCG)7/Y epileptogenic brain areas and depolarized cortical neurons. Allelic-dependent differences were also established in alternative splicing (AS) regulated by PUF60 and SAM68. As distinct features of Arx(GCG)7/Y mice, we detected eIF4A2 overexpression and translational suppression in cortex and primary neurons.
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elegans animals and a disorganized neurite network in murine primary neurons was consistent with an allelic-dependent secondary tubulinopathy. Decreased α-tubulin content was observed both in Arx mice and Arx/alr-1(KO) C. Gene ontology and protein–protein interaction analysis revealed that cytoskeleton, protein synthesis and splicing control are deregulated in an allelic-dependent manner. To address this question, a label-free quantitative proteomic approach was applied to neonatal brain of Arx knockout (ArxKO/Y) and knock-in polyalanine (Arx(GCG)7/Y) mice that are respectively models for XLAG and DEE1. It has been unknown whether the phenotypically diverse XLAG and DEE1 phenotypes may converge on shared pathways. X-linked lissencephaly with abnormal genitalia (XLAG) and developmental epileptic encephalopathy-1 (DEE1) are caused by mutations in the Aristaless-related homeobox (ARX) gene, which encodes a transcription factor responsible of brain development. SGL: subpial granular layer, Gp: globus pallidus, Th: thalamus, Hy: hypothalamus.
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Streams of ARX-positive post-mitotic neurons tangentially migrating around clusters of non-labelled progenitors were detected in the iSVZ (K) and oSVZ (L-M) of the MGE. In the lateral ganglionic eminence (LGE), ARX-expressing cells were present in the ventricular zone (VZ) and inner (iSVZ) and outer subventricular zone (oSVZ) (I) whereas only rare ARX-expressing cells were present in the VZ of the medial ganglionic eminence (MGE) (J). Several labelled cells were also detected in the putamen (Pu) and caudate nucleus (cn) (H). In the SVZ/IZ, several ARX-labelled cells were tangentially orientated (G). Cajal-Retzius cells were negative (E, inset). In the MZ, several nuclei positive for ARX had an orientation suggestive of inward migration towards the upper part of the cortical plate (CP) (E-F). In the intermediate zone (IZ), approximately 40 to 50% of the cells were ARXpositive (D). At 13 weeks of gestation (WG), the dorsal telencephalon was very strongly labelled (A-B), in particular neuronal progenitors of the ventricular (VZ) and subventricular zone (SVZ), in which the vast majority of cells were ARX-positive (B-C), including dividing cells as observed with H&E and Cresyl Violet staining of the nuclei (inset, C). ARX expression in the developing cortex and ganglionic eminences.