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Jozef Gecz - One of the best experts on this subject based on the ideXlab platform.
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Regulating transcriptional activity by phosphorylation: A new mechanism for the ARX homeodomain transcription factor.
'Public Library of Science (PLoS)', 2018Co-Authors: Tessa Mattiske, Jozef Gecz, Desiree Cloosterman, May H. Tan, Oliver Dearsley, Charles S Hii, Cheryl ShoubridgeAbstract:Aristaless-Related Homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in development. Here we identify that ARX protein is phosphorylated. Using mass spectrometry and in vitro kinase assays we identify phosphorylation at serines 37, 67 and 174. Through yeast-2-hybrid and CoIP we identified PICK1 (Protein interacting with C kinase 1) binding with the C-terminal region of ARX. PICK1 is a scaffold protein known to facilitate phosphorylation of protein partners by protein kinase C alpha (PRKCA). We confirm that ARX is phosphorylated by PRKCA and demonstrate phosphorylation at serine 174. We demonstrate that phosphorylation is required for correct transcriptional activity of the ARX protein using transcriptome-wide analysis of gene expression of phospho-null mutants (alanines replacing serines) compared to ARX wild-type (ARX-WT) overexpressed in pancreatic alpha TC cells. Compared to untransfected cells, ARX-WT overexpression significantly altered expression of 70 genes (Log2FC >+/-1.0, P-value
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Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation
Human molecular genetics, 2013Co-Authors: Kristie Lee, Tessa Mattiske, Kunio Kitamura, Jozef Gecz, Cheryl ShoubridgeAbstract:Intellectual disability (ID) is a highly prevalent disorder that affects 1-3% of the population. The Aristaless-Related Homeobox gene (ARX) is a frequently mutated X-linked ID gene and encodes a transcription factor indispensable for proper forebrain, testis and pancreas development. Polyalanine expansions account for over half of all mutations in ARX and clinically give rise to a spectrum of ID and seizures. To understand how the polyalanine expansions cause the clinical phenotype, we studied mouse models of the two most frequent polyalanine expansion mutations (Arx((GCG)7) and Arx(432-455dup24)). Neither model showed evidence of protein aggregates; however, a marked reduction of Arx protein abundance within the developing forebrain was striking. Examining the expression of known Arx target genes, we found a more prominent loss of Lmo1 repression in Arx((GCG7)/Y) compared with Arx(432-455dup24/Y) mice at 12.5 and 14.5 dpc, stages of peak neural proliferation and neurogenesis, respectively. Once neurogenesis concludes both mutant mouse models showed similar loss of Lmo1 repression. We propose that this temporal difference in the loss of Lmo1 repression may be one of the causes accounting for the phenotypic differences identified between the Arx((GCG)7)and Arx(432-455dup24) mouse models. It is yet to be determined what effect these mutations have on ARX protein in affected males in the human setting.
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PCR amplification and sequence analysis of GC-rich sequences: Aristaless-Related Homeobox example.
Methods in molecular biology (Clifton N.J.), 2013Co-Authors: May H. Tan, Jozef Gecz, Cheryl ShoubridgeAbstract:PCR amplification (followed by mutation scanning or direct sequencing) is a technique widely used in mutation detection and molecular studies of disease-causing genes, such as ARX. PCR amplification of high GC-rich regions encounters difficulties using conventional PCR procedures. Here, we present the strategies to amplify and sequence these GC-rich regions for the purposes of mutation screening and other molecular analyses.
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arx spectrum disorders making inroads into the molecular pathology
Human Mutation, 2010Co-Authors: Cheryl Shoubridge, Jozef Gecz, Tod FullstonAbstract:The Aristaless-Related Homeobox gene (ARX) is one of the most frequently mutated genes in a spectrum of X-chromosome phenotypes with intellectual disability (ID) as their cardinal feature. To date, close to 100 families and isolated cases have been reported to carry 44 different mutations, the majority of these (59%) being a result of polyalanine tract expansions. At least 10 well-defined clinical entities, including Ohtahara, Partington, and Proud syndromes, X-linked infantile spasms, X-linked lissencephaly with ambiguous genitalia, X-linked myoclonic epilepsy and nonsyndromic intellectual disability have been ascertained from among the patients with ARX mutations. The striking intra- and interfamilial pleiotropy together with genetic heterogeneity (same clinical entities associated with different ARX mutations) are becoming a hallmark of ARX mutations. Although males are predominantly affected, some mutations associated with malformation phenotypes in males also show a phenotype in carrier females. Recent progress in the study of the effect of ARX mutations through sophisticated animal (mice) and cellular models begins to provide crucial insights into the molecular function of ARX and associated molecular pathology, thus guiding future inquiries into therapeutic interventions.
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Ohtahara syndrome in a family with an ARX protein truncation mutation (c.81C>G/p.Y27X)
European Journal of Human Genetics, 2010Co-Authors: Tod Fullston, Jozef Gecz, Louise Brueton, Tracey Willis, Sunny Philip, Lesley Macpherson, Merran Finnis, Jenny MortonAbstract: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.81C>G (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.81C>G 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.
Cheryl Shoubridge - One of the best experts on this subject based on the ideXlab platform.
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early 17β estradiol treatment reduces seizures but not abnormal behaviour in mice with expanded polyalanine tracts in the Aristaless Related Homeobox gene arx
Neurobiology of Disease, 2021Co-Authors: Karagh E Loring, Kristie Lee, Tessa Mattiske, Aneta Zysk, Matilda R Jackson, Jeffrey L Noebels, Cheryl ShoubridgeAbstract:Abstract Children with severe intellectual disability have an increased prevalence of refractory seizures. Steroid treatment may improve seizure outcomes, but the mechanism remains unknown. Here we demonstrate that short term, daily delivery of an exogenous steroid 17β-estradiol (40 ng/g) in early postnatal life significantly reduced the number and severity of seizures, but did not improve behavioural deficits, in mice modelling mutations in the Aristaless-Related Homeobox gene (ARX), expanding the first (PA1) or second (PA2) polyalanine tract. Frequency of observed seizures on handling (n = 14/treatment/genotype) were significantly reduced in PA1 (32% reduction) and more modestly reduced in PA2 mice (14% reduction) with steroid treatment compared to vehicle. Spontaneous seizures were assessed (n = 7/treatment/genotype) at 7 weeks of age coinciding with a peak of seizure activity in untreated mice. PA1 mice treated with steroids no longer present with the most severe category of prolonged myoclonic seizures. Treated PA2 mice had an earlier onset of seizures coupled with a subsequent reduction in seizures later in postnatal life, with a complete absence of any seizures during the analysis at 7 weeks of age. Despite the reduction in seizures, 17β-estradiol treated mice showed no improvement in behavioural or cognitive outcomes in adulthood. For the first time we show that these deficits due to mutations in Arx are already present before seizure onset and do not worsen with seizures. ARX is a transcription factor and Arx PA mutant mice have deregulated transcriptome profiles in the developing embryonic brain. At postnatal day 10, treatment completion, RNAseq identified 129 genes significantly deregulated (Log2FC > ± 0.5, P-value
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Regulating transcriptional activity by phosphorylation: A new mechanism for the ARX homeodomain transcription factor.
'Public Library of Science (PLoS)', 2018Co-Authors: Tessa Mattiske, Jozef Gecz, Desiree Cloosterman, May H. Tan, Oliver Dearsley, Charles S Hii, Cheryl ShoubridgeAbstract:Aristaless-Related Homeobox (ARX) gene encodes a paired-type homeodomain transcription factor with critical roles in development. Here we identify that ARX protein is phosphorylated. Using mass spectrometry and in vitro kinase assays we identify phosphorylation at serines 37, 67 and 174. Through yeast-2-hybrid and CoIP we identified PICK1 (Protein interacting with C kinase 1) binding with the C-terminal region of ARX. PICK1 is a scaffold protein known to facilitate phosphorylation of protein partners by protein kinase C alpha (PRKCA). We confirm that ARX is phosphorylated by PRKCA and demonstrate phosphorylation at serine 174. We demonstrate that phosphorylation is required for correct transcriptional activity of the ARX protein using transcriptome-wide analysis of gene expression of phospho-null mutants (alanines replacing serines) compared to ARX wild-type (ARX-WT) overexpressed in pancreatic alpha TC cells. Compared to untransfected cells, ARX-WT overexpression significantly altered expression of 70 genes (Log2FC >+/-1.0, P-value
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extensive phenotyping of two arx polyalanine expansion mutation mouse models that span clinical spectrum of intellectual disability and epilepsy
Neurobiology of Disease, 2017Co-Authors: Matilda R Jackson, Tessa Mattiske, Emily J Jaehne, Ezgi Ozturk, Bernhard T Baune, Terence J Obrien, Nigel C Jones, Cheryl ShoubridgeAbstract:Abstract The Aristaless- Related Homeobox gene ( ARX ) is a known intellectual disability (ID) gene that frequently presents with X-linked infantile spasm syndrome as a comorbidity. ID with epilepsy in children is a chronic and devastating disorder that has poor treatment options and disease outcomes. To gain a better understanding of the role that mutations in ARX play in ID and epilepsy, we investigate ARX patient mutations modelled in mice. Over half of all ARX mutations result from expansions of the first two polyalanine (PA1 and PA2 respectively) tracts. However, phenotypic data for the mouse modelling the more frequent ARX PA2 dup24 mutation in patients has not been reported and constitutes a barrier to understanding the molecular mechanisms involved. Here we report the first comprehensive analysis of postnatal outcomes for mice modelling disease-causing expansions to both PA1 and PA2 tracts. Both strains were found to have impaired learning and memory, reduced activity, increased anxiety and reduced sociability; with PA1 mice generally displaying greater behavioural deficits in keeping with the more severe phenotype reported in patients. In agreement with previous reports, 70% of PA1 males exhibit myoclonic seizures by two months of age, with the first observed at P18. In this report, we show 80% of PA2 males also display myoclonic seizures, with the first observed at P19. Consistent with patient phenotypes, we observe large variations in seizure progression and severity for both PA1 and PA2 individual mice. The generation of this comprehensive baseline data is a necessary step on the path to the development of therapies to improve patient outcomes.
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X-Linked Lissencephaly With Absent Corpus Callosum and Abnormal Genitalia
SAGE Publishing, 2017Co-Authors: David Coman Fracp, Cheryl Shoubridge, Tom Fullston, Richard Leventer, Flora Wong Fracp, Simon Nazaretian Frcpa, Ian Simpson Frcpa, Josef Gecz, George Mcgillivray FracpAbstract:X-linked lissencephaly with abnormal genitalia is a rare and devastating syndrome. The authors present an infant with a multisystem phenotype where the intestinal manifestations were as life limiting as the central nervous system features. Severe chronic diarrhea resulted in failure to thrive, dehydration, electrolyte derangements, long-term hospitalization, and prompted transition to palliative care. Other multisystem manifestations included megacolon, colitis, pancreatic insufficiency hypothalamic dysfunction, hypothyroidism, and hypophosphatasia. A novel Aristaless-Related Homeobox gene mutation, c.1136G>T/p.R379L, was identified. This case contributes to the clinical, histological, and molecular understanding of the multisystem nature of this disorder, especially the role of ARX in the development of the enteroendocrine system
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Reduced polyalanine-expanded Arx mutant protein in developing mouse subpallium alters Lmo1 transcriptional regulation
Human molecular genetics, 2013Co-Authors: Kristie Lee, Tessa Mattiske, Kunio Kitamura, Jozef Gecz, Cheryl ShoubridgeAbstract:Intellectual disability (ID) is a highly prevalent disorder that affects 1-3% of the population. The Aristaless-Related Homeobox gene (ARX) is a frequently mutated X-linked ID gene and encodes a transcription factor indispensable for proper forebrain, testis and pancreas development. Polyalanine expansions account for over half of all mutations in ARX and clinically give rise to a spectrum of ID and seizures. To understand how the polyalanine expansions cause the clinical phenotype, we studied mouse models of the two most frequent polyalanine expansion mutations (Arx((GCG)7) and Arx(432-455dup24)). Neither model showed evidence of protein aggregates; however, a marked reduction of Arx protein abundance within the developing forebrain was striking. Examining the expression of known Arx target genes, we found a more prominent loss of Lmo1 repression in Arx((GCG7)/Y) compared with Arx(432-455dup24/Y) mice at 12.5 and 14.5 dpc, stages of peak neural proliferation and neurogenesis, respectively. Once neurogenesis concludes both mutant mouse models showed similar loss of Lmo1 repression. We propose that this temporal difference in the loss of Lmo1 repression may be one of the causes accounting for the phenotypic differences identified between the Arx((GCG)7)and Arx(432-455dup24) mouse models. It is yet to be determined what effect these mutations have on ARX protein in affected males in the human setting.
Jeffrey A. Golden - One of the best experts on this subject based on the ideXlab platform.
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identification and validation of the phosphorylation sites on Aristaless Related Homeobox protein
Bioscience Reports, 2020Co-Authors: Jeffrey A. Golden, Xiuyu Shi, Wenbo Lin, Xiang Gao, Wen Xie, Tao TaoAbstract:The Aristaless-Related Homeobox protein (ARX) is a transcription factor expressed in the developing forebrain, skeletal muscle, pancreas, testis, and a variety of other tissues. It is known to have context-dependent transcriptional activator and repressor activity, although how it can achieve these opposing functions remains poorly understood. We hypothesized phosphorylation status might play a role in pivoting ARX between functioning as an activator or repressor. To gain further mechanistic insight as to how ARX functions, we identified multiple phosphorylation sites on ARX. We further established PKA as the kinase that phosphorylates ARX at least at Ser266 in mice. Two other kinases, CK2α and CDK4/cyclin D1, were also identified as kinases that phosphorylate ARX in vitro. Unexpectedly, phosphorylation status did not change either the nuclear localization or transcriptional function of ARX.
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Arx Expression Suppresses Ventralization of the Developing Dorsal Forebrain
Nature Publishing Group, 2019Co-Authors: Youngshin Lim, Il-taeg Cho, Ginam Cho, Xiuyu Shi, Judith B. Grinspan, Jeffrey A. GoldenAbstract:Abstract Early brain development requires a tight orchestration between neural tube patterning and growth. How pattern formation and brain growth are coordinated is incompletely understood. Previously we showed that Aristaless-Related Homeobox (ARX), a paired-like transcription factor, regulates cortical progenitor pool expansion by repressing an inhibitor of cell cycle progression. Here we show that ARX participates in establishing dorsoventral identity in the mouse forebrain. In Arx mutant mice, ventral genes, including Olig2, are ectopically expressed dorsally. Furthermore, Gli1 is upregulated, suggesting an ectopic activation of SHH signaling. We show that the ectopic Olig2 expression can be repressed by blocking SHH signaling, implicating a role for SHH signaling in Olig2 induction. We further demonstrate that the ectopic Olig2 accounts for the reduced Pax6 and Tbr2 expression, both dorsal specific genes essential for cortical progenitor cell proliferation. These data suggest a link between the control of dorsoventral identity of progenitor cells and the control of their proliferation. In summary, our data demonstrate that ARX functions in a gene regulatory network integrating normal forebrain patterning and growth, providing important insight into how mutations in ARX can disrupt multiple aspects of brain development and thus generate a wide spectrum of neurodevelopmental phenotypes observed in human patients
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Identification of Arx transcriptional targets in the developing basal forebrain. Human molecular genetics. 2008; 17(23):3740–60. doi: 10
2016Co-Authors: Carl T. Fulp, Ginam Cho, Eric D Marsh, Ilya M. Nasrallah, Patricia A. Labosky, Jeffrey A. GoldenAbstract:Mutations in the Aristaless-Related Homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understandhow the identifiedgenes are involved inneural development,weusedgeneset enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These ana-lyses identified a subset of genes in the ArxGRN that are sharedwith that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, bot
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conditional loss of arx from the developing dorsal telencephalon results in behavioral phenotypes resembling mild human arx mutations
Cerebral Cortex, 2015Co-Authors: Jacqueline C Simonet, Jeffrey A. Golden, Eric D Marsh, Nicole C SunnenAbstract:Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses.
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arx regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of cdkn1c
Cerebral Cortex, 2015Co-Authors: Gaia Colasante, Jeffrey A. Golden, Ginam Cho, Jacqueline C Simonet, Raffaele A Calogero, Stefania Crispi, Alessandro Sessa, Vania BroccoliAbstract:Mutations in the Aristaless-Related Homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx−/Y mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.
Marie Mangelsdorf - One of the best experts on this subject based on the ideXlab platform.
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Aristaless Related Homeobox gene the gene responsible for west syndrome and Related disorders is a groucho transducin like enhancer of split dependent transcriptional repressor
Neuroscience, 2007Co-Authors: O Mckenzie, Jozef Gecz, Cheryl Shoubridge, Merran Finnis, Marie Mangelsdorf, I Ponte, Gaia Colasante, Stefano StifaniAbstract:Aristaless-Related Homeobox gene (ARX) is an important paired-type Homeobox gene involved in the development of human brain. The ARX gene mutations are a significant contributor to various forms of X-chromosome-linked mental retardation with and without additional features including epilepsy, lissencephaly with abnormal genitalia, hand dystonia or autism. Here we demonstrate that the human ARX protein is a potent transcriptional repressor, which binds to Groucho/transducin-like enhancer of split (TLE) co-factor proteins and the TLE1 in particular through its octapeptide (Engrailed homology repressor domain (eh-1) homology) domain. We show that the transcription repression activity of ARX is modulated by two strong repression domains, one located within the octapeptide domain and the second in the region of the polyalanine tract 4, and one activator domain, the Aristaless domain. Importantly, we show that the transcription repression activity of ARX is affected by various naturally occurring mutations. The introduction of the c.98T>C (p.L33P) mutation results in the lack of binding to TLE1 protein and relaxed transcription repression. The introduction of the two most frequent ARX polyalanine tract expansion mutations increases the repression activity in a manner dependent on the number of extra alanines. Interestingly, deletions of alanine residues within polyalanine tracts 1 and 2 show low or no effect. In summary we demonstrate that the ARX protein is a strong transcription repressor, we identify novel ARX interacting proteins (TLE) and offer an explanation of a molecular pathogenesis of some ARX mutations, including the most frequent ARX mutations, the polyalanine tract expansion mutations, c.304ins(GCG)7 and c.428_451dup.
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xlmr in mrx families 29 32 33 and 38 results from the dup24 mutation in the arx Aristaless Related Homeobox gene
BMC Medical Genetics, 2005Co-Authors: Monica L Stepp, Merran Finnis, Marie Mangelsdorf, Lauren A Cason, David Macgregor, Andrée Macmillan, Jeanette Ja Holden, Elke Holinskifeder, Jozef GeczAbstract:Background X-linked mental retardation (XLMR) is the leading cause of mental retardation in males. Mutations in the ARX gene in Xp22.1 have been found in numerous families with both nonsyndromic and syndromic XLMR. The most frequent mutation in this gene is a 24 bp duplication in exon 2. Based on this fact, a panel of XLMR families linked to Xp22 was tested for this particular ARX mutation.
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BMC Medical Genetics BioMed Central
2005Co-Authors: Lauren A Cason, Jozef Gecz, Merran Finnis, Marie Mangelsdorf, Elke Holinski-feder, David Macgregor, Andrée Macmillan, Jeanette Ja Holden, Roger E Stevenson, Charles E SchwartzAbstract:Research article XLMR in MRX families 29, 32, 33 and 38 results from the dup24 mutation in the ARX (Aristaless Related Homeobox) gen
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infantile spasms dystonia and other x linked phenotypes caused by mutations in Aristaless Related Homeobox gene arx
Brain & Development, 2002Co-Authors: Petter Stromme, Jozef Gecz, Marie Mangelsdorf, Ingrid E SchefferAbstract:Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless Related Homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations.
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communication infantile spasms dystonia and other x linked phenotypes caused by mutations in Aristaless Related Homeobox gene arx
2002Co-Authors: Petter Stromme, Marie Mangelsdorf, Ingrid E SchefferAbstract:Clinical data from 50 mentally retarded (MR) males in nine X-linked MR families, syndromic and non-specific, with mutations (duplication, expansion, missense, and deletion mutations) in the Aristaless Related Homeobox gene, ARX, were analysed. Seizures were observed with all mutations and occurred in 29 patients, including one family with a novel myoclonic epilepsy syndrome associated with the missense mutation. Seventeen patients had infantile spasms. Other phenotypes included mild to moderate MR alone, or with combinations of dystonia, ataxia or autism. These data suggest that mutations in the ARX gene are important causes of MR, often associated with diverse neurological manifestations. q 2002 Elsevier Science B.V. All rights reserved.
Eric D Marsh - One of the best experts on this subject based on the ideXlab platform.
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Identification of Arx transcriptional targets in the developing basal forebrain. Human molecular genetics. 2008; 17(23):3740–60. doi: 10
2016Co-Authors: Carl T. Fulp, Ginam Cho, Eric D Marsh, Ilya M. Nasrallah, Patricia A. Labosky, Jeffrey A. GoldenAbstract:Mutations in the Aristaless-Related Homeobox (ARX) gene are associated with multiple neurologic disorders in humans. Studies in mice indicate Arx plays a role in neuronal progenitor proliferation and development of the cerebral cortex, thalamus, hippocampus, striatum, and olfactory bulbs. Specific defects associated with Arx loss of function include abnormal interneuron migration and subtype differentiation. How disruptions in ARX result in human disease and how loss of Arx in mice results in these phenotypes remains poorly understood. To gain insight into the biological functions of Arx, we performed a genome-wide expression screen to identify transcriptional changes within the subpallium in the absence of Arx. We have identified 84 genes whose expression was dysregulated in the absence of Arx. This population was enriched in genes involved in cell migration, axonal guidance, neurogenesis, and regulation of transcription and includes genes implicated in autism, epilepsy, and mental retardation; all features recognized in patients with ARX mutations. Additionally, we found Arx directly repressed three of the identified transcription factors: Lmo1, Ebf3 and Shox2. To further understandhow the identifiedgenes are involved inneural development,weusedgeneset enrichment algorithms to compare the Arx gene regulatory network (GRN) to the Dlx1/2 GRN and interneuron transcriptome. These ana-lyses identified a subset of genes in the ArxGRN that are sharedwith that of the Dlx1/2 GRN and that are enriched in the interneuron transcriptome. These data indicate Arx plays multiple roles in forebrain development, bot
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conditional loss of arx from the developing dorsal telencephalon results in behavioral phenotypes resembling mild human arx mutations
Cerebral Cortex, 2015Co-Authors: Jacqueline C Simonet, Jeffrey A. Golden, Eric D Marsh, Nicole C SunnenAbstract:Mutations in the Aristaless-Related Homeobox (ARX) gene cause structural anomalies of the brain, epilepsy, and neurocognitive deficits in children. During forebrain development, Arx is expressed in both pallial and subpallial progenitor cells. We previously demonstrated that elimination of Arx from subpallial-derived cortical interneurons generates an epilepsy phenotype with features overlapping those seen in patients with ARX mutations. In this report, we have selectively removed Arx from pallial progenitor cells that give rise to the cerebral cortical projection neurons. While no discernable seizure activity was recorded, these mice exhibited a peculiar constellation of behaviors. They are less anxious, less social, and more active when compared with their wild-type littermates. The overall cortical thickness was reduced, and the corpus callosum and anterior commissure were hypoplastic, consistent with a perturbation in cortical connectivity. Taken together, these data suggest that some of the structural and behavioral anomalies, common in patients with ARX mutations, are specifically due to alterations in pallial progenitor function. Furthermore, our data demonstrate that some of the neurobehavioral features found in patients with ARX mutations may not be due to on-going seizures, as is often postulated, given that epilepsy was eliminated as a confounding variable in these behavior analyses.
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arx is required for specification of the zona incerta and reticular nucleus of the thalamus
Journal of Neuropathology and Experimental Neurology, 2014Co-Authors: Nicole C Sunnen, Eric D Marsh, Jacqueline C Simonet, Jeffrey A. GoldenAbstract:Mutations in the Aristaless-Related Homeobox ( ARX ) gene result in a spectrum of structural and functional nervous system disorders including lissencephaly, movement disorders, intellectual disabilities, and epilepsy. Some patients also have symptoms indicating hypothalamic dysfunction, but little is known about the role of ARX in diencephalic development. To begin evaluating diencephalic defects, we examined the expression of a panel of known genes and gene products that label specific diencephalic nuclei in 2 different Arx mutant mouse lines at E18.5. Male mice engineered to have a polyalanine expansion mutation ( Arx(GCG)7/Y ) revealed no expression differences in any diencephalic nucleus when compared with wild-type littermates. In contrast, mice null for Arx ( Arx-/Y ) lost expression of specific markers of the thalamic reticular nucleus and zona incerta (ZI) while retaining expression in other thalamic nuclei and in the hypothalamus. Tyrosine hydroxylase, a marker of the dopaminergic A13 subnucleus of ZI, was among those lost, suggesting a requirement for Arx in normal thalamic reticular nucleus and ZI development and, specifically, for A13 dopaminergic fate. Because the ZI and A13 regions make connections to several hypothalamic nuclei, such misspecification may contribute to the “hypothalamic dysfunction” observed in some patients.
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developing models of Aristaless Related Homeobox mutations
2012Co-Authors: Eric D Marsh, Jeffrey A. GoldenAbstract:Mutations in the Aristaless-Related Homeobox gene (ARX) have been causally linked to a variety of neurological conditions, particularly, infantile spasms syndrome. ARX is a developmentally regulated Homeobox transcription factor with expression both in the ganglionic eminence and the cortical ventricular zone early in development. Postnatally, the expression pattern is restricted to GABAergic neurons in the cortex and basal ganglia. During development, ARX functions primarily as a transcriptional repressor: modulating migration and fate specification of interneurons and controlling ventricular zone proliferation. How loss of function of ARX leads to an epilepsy phenotype is poorly understood. Three genetically modified mice lines have been generated to address this issue. These models each develop epilepsy and all have changes in interneuron subtype patterns strongly implicating alterations of interneuron development as a cause of epilepsy. Analysis of these models will both further the molecular understanding of the function of ARX and allow dissection of the pathophysiological properties of the ARX Related epilepsies. This chapter will review the current knowledge of the function of Arx, the Arx mouse models, and discuss how these models can lead to a better understanding of the role of interneuron loss in the development of epilepsy during early childhood.
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Aristaless Related Homeobox mutations
Epilepsia, 2010Co-Authors: Eric D Marsh, Jeffrey A. GoldenAbstract:Mutations in the Aristaless-Related Homeobox gene (ARX) are linked to infantile spasms and other developmental epilepsies. How loss of Arx leads to epilepsy is not well understood. This review will discuss the spectrum of Arx disorders and the emerging evidence, from animal models, of the function of Arx during development and the potential role in generating an epilepsy phenotype. For an expanded treatment of this topic see Jasper's Basic Mechanisms of the Epilepsies, Fourth Edition (Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, eds) published by Oxford University Press (available on the National Library of Medicine Bookshelf [NCBI] at www. ncbi.nlm.nih.gov/books).