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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Investigation of a critical region for an X-linked mental retardation (XLMR) locus led us to identify a novel Aristaless related homeobox gene (ARX ). Inherited and de novo ARX mutations, including missense mutations and in frame duplications/insertions leading to expansions of polyalanine tracts in ARX, were found in nine familial and one sporadic case of MR. In contrast to other genes involved in XLMR, ARX expression is specific to the telencephalon and ventral thalamus. Notably there is an absence of expression in the cerebellum throughout development and also in adult. The absence of detectable brain malformations in patients suggests that ARX may have an essential role, in mature neurons, required for the development of cognitive abilities.
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PMID:ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation. 1197 79

Arx is a homeobox-containing gene with a high degree of sequence similarity between mouse and zebrafish. Arx is expressed in the forebrain and floor plate of the developing central nervous systems of these vertebrates and in the presumptive cortex of fetal mice. Our goal was to identify genes in Xp22.1-p21.3 involved in human neuronal development. Our in silico search for candidate genes noted that annotation of a human Xp22 PAC (RPCI1-258N20) sequence (GenBank Accession No. AC002504) identified putative exons consistent with an Arx homologue in Xp22. Northern blot analysis showed that a 3.3kb human ARX transcript was expressed at high levels in fetal brain. A 5.9kb transcript was expressed in adult heart, skeletal muscle, and liver with very faint expression in other adult tissues, including brain. In situ hybridization of ARX in human fetal brain sections at various developmental stages showed the highest expression in neuronal precursors in the germinal matrix of the ganglionic eminence and in the ventricular zone of the telencephalon. Expression was also observed in the hippocampus, cingulate, subventricular zone, cortical plate, caudate nucleus, and putamen. The expression pattern suggests that ARX is involved in the differentiation and maintenance of specific neuronal cell types in the human central nervous system. We also mapped the murine Arx gene to the mouse genome using a mouse/hamster radiation hybrid panel and showed that Arx and ARX are orthologues. Therefore, investigations in model vertebrates may provide insight into the role of ARX in development. The recent identification of ARX mutations in patients with various forms of mental retardation make such studies in model organisms even more compelling.
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PMID:Human ARX gene: genomic characterization and expression. 1235 45

Two families, originally diagnosed as having nonsyndromic X-linked mental retardation (NSXLMR), were reviewed when it was shown that they had a 24-bp duplication (428-45 1dup(24bp)) in the ARX gene [Stromme et al., 2002: Nat Genet 30:441-445]. This same duplication had also been found in three other families: one with X-linked infantile spasms and hypsarrhythmia (X-linked West syndrome, MIM 308350) and two with XLMR and dystonic movements of the hands (Partington syndrome, MIM 309510). On review, manifestations of both West and Partington syndromes were found in some individuals from both families. In addition, it was found that one individual had autism and two had autistic behavior, one of whom had epilepsy. The degree of mental retardation ranged from mild to severe. A GCG trinucleotide expansion (GCG)10+7 and a deletion of 1,517 bp in the ARX gene have also been found in association with the West syndrome, and a missense mutation (1058C>T) in a family with a newly recognized form of myoclonic epilepsy, severe mental retardation, and spastic paraplegia [Scheffer et al., 2002: Neurology, in press]. Evidently all these disorders are expressions of mutations in the same gene. It remains to be seen what proportions of patients with infantile spasms, focal dystonia, autism, epilepsy, and nonsyndromic mental retardation are accounted for by mutations in the ARX gene.
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PMID:Variable expression of mental retardation, autism, seizures, and dystonic hand movements in two families with an identical ARX gene mutation. 1237 46

The human aristaless-related homeobox ( ARX) gene is mutated in several patients with X-linked mental retardation and/or other neurologic pathologies. We report the isolation and expression pattern of a Xenopus arx gene. Similar to other vertebrate arx genes, Xenopus arx is expressed in the developing telencephalon, diencephalon, and floor plate.
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PMID:The Xenopus arx gene is expressed in the developing rostral forebrain. 1253 26

The novel Aristaless related homeobox gene, ARX, is widely expressed in the brain and is thought to play a key role in the regulation of brain development. Neurological phenotypes caused by ARX mutations have recently started to unfold. We describe a 72 year old man with X-linked mental retardation due to a 24 bp duplication mutation in exon 2 of the ARX gene. Cerebral MRI showed bilateral cystic-like cavities in both the cerebral and cerebellar hemispheres. No retraction or expansion in neighbouring parenchyma was observed, there was no history of acute neurological impairment, and no risk factors for cerebrovascular disease were found. The lesions appeared to be congenital and represented benign developmental cysts, possibly caused by the ARX mutation.
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PMID:Brain cysts associated with mutation in the Aristaless related homeobox gene, ARX. 1264 86

Mental retardation (MR) and epilepsy are both heterogeneous syndromes based on dysfunction in the brain and they are often closely associated. Hence, there should be some overlap in the underlying pathomechanisms, particularly when both syndromes result from genetic abnormalities, either polygenic or monogenic. Some 50 monogenic causes of MR have been found in genes localized on the X-chromosome and are responsible for X-linked MR. In contrast, monogenic causes of about 30 epilepsy syndromes are transmitted as an autosomal trait. Early this year, an X-chromosome-linked, Aristaless-related, homeobox gene, ARX, was found to be associated with both X-linked MR and epilepsy. The epilepsy phenotypes included West syndrome and other epilepsy phenotypes, indicating the genetic basis of the X-linked West syndrome. Another report implied that the ARX molecule plays a crucial role in cognitive function. These findings provide solid evidence for the relationship between MR and epilepsy at a molecular level, opening a new avenue for understanding the pathogeneses of MR associated with epilepsy.
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PMID:X-linked mental retardation and epilepsy: pathogenetic significance of ARX mutations. 1268 93

Mental retardation (MR) is a symptom in a large group of clinical conditions and affects around 3% of the population. MR is divided into syndromic, if it is characterized by distinctive clinical features and nonspecific when mental retardation is the only defining manifestation. Although genetic causes of X-linked mental retardation (XLMR) are heterogenous and complex, recent findings have led to the identification of an increasing number of genes involved in these conditions. Eight genes involved in nonspecific X-linked mental retardation have been identified so far, including FMR2, GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, TM4SF2, and FACL4. Four other MECP2, RSK2, ARX, ATR-X are involved in syndromic and nonspecific forms of MR. Recent research has shown that these genes encode for proteins involved in signaling pathways which regulate cytoskeleton organization, synaptic vesicle transport and establishment of connections between neuronal cells. These findings provide insight into the molecular mechanisms of crucial processes for the development of intellectual and cognitive functions.
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PMID:[Monogenic causes of nonspecific X-linked mental retardation molecular aspects]. 1281 Sep 81

X-linked lissencephaly with abnormal genitalia (XLAG) is a distinct form of lissencephaly associated with absent corpus callosum. Recently, forms of syndromic and nonspecific X-linked mental retardation have been found to be associated with mutations in the Aristaless-related homeobox gene ARX. The authors assessed ARX as a candidate gene for XLAG in a genetic analysis of neuronal migration disorders and found two different point mutations in two XLAG pedigrees affecting the homeodomain of the protein, confirming that ARX is a causative gene for XLAG.
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PMID:ARX mutations in X-linked lissencephaly with abnormal genitalia. 1287 90

We recently identified mutations of ARX in nine genotypic males with X-linked lissencephaly with abnormal genitalia (XLAG), and in several female relatives with isolated agenesis of the corpus callosum (ACC). We now report 13 novel and two recurrent mutations of ARX, and one nucleotide change of uncertain significance in 20 genotypic males from 16 families. Most had XLAG, but two had hydranencephaly and abnormal genitalia, and three males from one family had Proud syndrome or ACC with abnormal genitalia. We obtained detailed clinical information on all 29 affected males, including the nine previously reported subjects. Premature termination mutations consisting of large deletions, frameshifts, nonsense mutations, and splice site mutations in exons 1 to 4 caused XLAG or hydranencephaly with abnormal genitalia. Nonconservative missense mutations within the homeobox caused less severe XLAG, while conservative substitution in the homeodomain caused Proud syndrome. A nonconservative missense mutation near the C-terminal aristaless domain caused unusually severe XLAG with microcephaly and mild cerebellar hypoplasia. In addition, several less severe phenotypes without malformations have been reported, including mental retardation with cryptogenic infantile spasms (West syndrome), other seizure types, dystonia or autism, and nonsyndromic mental retardation. The ARX mutations associated with these phenotypes have included polyalanine expansions or duplications, missense mutations, and one deletion of exon 5. Together, the group of phenotypes associated with ARX mutations demonstrates remarkable pleiotropy, but also comprises a nearly continuous series of developmental disorders that begins with hydranencephaly, lissencephaly, and agenesis of the corpus callosum, and ends with a series of overlapping syndromes with apparently normal brain structure.
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PMID:Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. 1472 18

The newly identified gene, ARX, when mutated has been shown to cause both syndromic and nonsyndromic forms of mental retardation. It seems that the less severe forms are due to polyalanine expansions and missense mutations in the gene. We screened 682 developmentally retarded males for polyalanine expansions in ARX in order to examine the contribution of ARX mutations to the causes of developmental retardation. We also reinvestigated 11 putative MRX and three MR families where no cause of mental retardation had been found, by mutational analysis of ARX. Mutational analysis was also performed in 11 probands with autism from families with two or more affected males. We find that previously described polyalanine expansions of ARX are not a common cause of mental retardation.
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PMID:Screening of the ARX gene in 682 retarded males. 1519 82


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