Human ARX gene: genomic characterization and expression

Ohira, R; Zhang, Y.-H; Guo, Weiwen; Dipple, Katrina M.; Shih, Shu‐Fu; Doerr, Jeanette R.; Huang, Bing-Ling; Fu, Lei; Abu-Khalil, Amir; Geschwind, Daniel H.; McCabe, Edward R.B.

doi:10.1016/s1096-7192(02)00126-9

Cited by 56 publications

(45 citation statements)

References 33 publications

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“…The ARX protein contains a Q (50) paired-type homeodomain, a C-terminal aristaless domain, and an N-terminal octapeptide and acts as a nuclear transcriptional regulator to activate or inhibit gene expression (Seufert et al 2005, McKenzie et al 2007, Biressi et al 2008, Fullenkamp & El-Hodiri 2008, Colasante et al 2009). The ARX gene encodes a 562-amino acid protein (Ohira et al 2002, Stromme et al 2002 with four characteristic polyalanine (PolyA) tracts where most of the ARX mutations occur (Gecz et al 2006). ARX mutations in humans lead to multiple neurological disorders including X-linked lissencephaly with or without ambiguous genitalia (XLAG syndrome), epilepsy, and mental retardation.…”

Section: Introductionmentioning

confidence: 99%

ARX/Arx is expressed in germ cells during spermatogenesis in both marsupial and mouse

Pask

et al. 2014

Reproduction

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The X-linked aristaless gene, ARX, is essential for the development of the gonads, forebrain, olfactory bulb, pancreas, and skeletal muscle in mice and humans. Mutations cause neurological diseases, often accompanied by ambiguous genitalia. There are a disproportionately high number of testis and brain genes on the human and mouse X chromosomes. It is still unknown whether the X chromosome accrued these genes during its evolution or whether genes that find themselves on the X chromosome evolve such roles. ARX was originally autosomal in mammals and remains so in marsupials, whereas in eutherian mammals it translocated to the X chromosome. In this study, we examined autosomal ARX in tammars and compared it with the X-linked Arx in mice. We detected ARX mRNA in the neural cells of the forebrain, midbrain and hindbrain, and olfactory bulbs in developing tammars, consistent with the expression in mice. ARX was detected by RT-PCR and mRNA in situ hybridization in the developing tammar wallaby gonads of both sexes, suggestive of a role in sexual development as in mice. We also detected ARX/Arx mRNA in the adult testis in both tammars and mice, suggesting a potential novel role for ARX/Arx in spermiogenesis. ARX transcripts were predominantly observed in round spermatids. Arx mRNA localization distributions in the mouse adult testis suggest that it escaped meiotic sex chromosome inactivation during spermatogenesis. Our findings suggest that ARX in the therian mammal ancestor already played a role in male reproduction before it was recruited to the X chromosome in eutherians.

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Section: Introductionmentioning

confidence: 99%

ARX/Arx is expressed in germ cells during spermatogenesis in both marsupial and mouse

Pask

et al. 2014

Reproduction

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“…Cells expressing GST-tagged proteins were sonicated in 1ϫ phosphate-buffered saline, and the supernatants were incubated with glutathione-Sepharose 4B beads. The purified Arx-His 6 and lysates of cells expressing EGFP-tagged Arx and its mutants were incubated with glutathione-Sepharose 4B beads saturated with either imp␤1, imp4, imp9, and imp13-GST or GST for 3 h at 4°C. Washed beads were mixed with protein loading buffer and boiled for SDS-PAGE-Western blotting.…”

Section: Methodsmentioning

confidence: 99%

“…The aristaless-related homeobox (ARX) 4 protein, a paired-type homeodomain containing protein, is mutated in multiple human conditions (3)(4)(5). ARX is expressed most strongly in the brain (6) and is important for development of the forebrain, pancreas, and testis (7). Arx proteins are highly conserved ( Fig.…”

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confidence: 99%

The Roles of Multiple Importins for Nuclear Import of Murine Aristaless-related Homeobox Protein

Lin

Cai

et al. 2009

Journal of Biological Chemistry

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Nuclear import of proteins with nuclear localization signals (NLSs) is mediated by shuttling carriers, the importins. Some cargoes display more than a single NLS, and among these are homeodomain proteins such as Arx, which is critical for development of multiple tissues. Arx has two functional NLSs. The present studies show that several pathways can import Arx via its NLS2, which is within its DNA binding homeodomain. Using an in vitro nuclear import assay, we show that import of Arx via NLS2 can be mediated by importin ␤1, importin 9, or importin 13, with binding being strongest to importin ␤1. All binding is sensitive to RanGTP. Experiments based on precise domain deletions indicate that NLS2 binds imp␤1, imp9, and imp13 and includes both an importin binding subdomain and a regulatory subdomain with arginine residues being important for function. Moreover, Arx can be co-precipitated with these importins when NLS2 is present. Although nuclear import of Arx can be mediated by these three importin ␤s, importin ␤1 seems to play the major role judging from in vivo small interfering RNA ablations and the in vitro import assay. This is the first evidence to show the role of importin ␤1 in nuclear import of paired-type homeodomain proteins. We propose a novel and possibly quite general mechanism for nuclear import of paired-type homeodomain proteins which is critical for development.Precise nucleocytoplasmic distribution of the homeodomain superfamily of transcription factors is critical for development. Several studies have demonstrated that NLS activity resides within the 60-amino acid DNA binding homeodomain itself, which is composed of three helices (1, 2). The "paired type" subgroup of the superfamily is characterized by a set of highly conserved residues. There are 26 members of this subgroup in man. The aristaless-related homeobox (ARX) 4 protein, a paired-type homeodomain containing protein, is mutated in multiple human conditions (3-5). ARX is expressed most strongly in the brain (6) and is important for development of the forebrain, pancreas, and testis (7). Arx proteins are highly conserved (Fig. 1) and contain 562 amino acids (564 amino acids in mouse) with four poly(A) (alanine) tracts of variable length, a paired-type homeodomain, and a conserved "aristaless" domain (8). Endogenous Arx was found in the nucleus of some types of nerve cells (9, 10). Because Arx has a molecular mass larger than 60 kDa, its nuclear import is likely to be signal-dependent. Three putative basic NLSs in Arx have been proposed (8, 11): NLS1 from aa 82 to 89, BC1 from aa 327 to 334, and BC2 from aa 381 to 388 (Fig. 1). It is not clear whether or how these putative NLSs function in the nuclear localization of Arx.As for other trinucleotide-repeat-containing genes (12, 13), the first poly(A) tract can expand in Arx. Expansion of this tract or loss of the 3Ј aristaless domain in Arx are both associated with infantile spasms syndrome and mental retardation (14, 15). Moreover, expansion of the first poly(A) tract of Arx results in for...

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“…The Aristaless-related homeobox (ARX) gene, on chromosome Xp22, is a transcription factor that belongs to a family of paired class homeobox genes, and plays an important role in embryogenesis, especially in the development of the central nervous system [88]. To date, ARX mutations have been identified in about 10 different clinical conditions, with or without brain malformations [89][90][91].…”

Section: Aristaless-related Homeoboxmentioning

confidence: 99%

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

2014

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Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.

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Human ARX gene: genomic characterization and expression

Cited by 56 publications

References 33 publications

ARX/Arx is expressed in germ cells during spermatogenesis in both marsupial and mouse

ARX/Arx is expressed in germ cells during spermatogenesis in both marsupial and mouse

The Roles of Multiple Importins for Nuclear Import of Murine Aristaless-related Homeobox Protein

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

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