Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Development and implementation of high-density DNA arrays demonstrated the important role of copy number changes on the X chromosome in the etiology of developmental delay and mental retardation (MR). We describe two unrelated patients with developmental delay due to similar interstitial duplications at Xp21-p22. The first patient is a 6-month-old male with multiple affected family members including many females. The second patient is a 5-year-old adopted female. In both patients, chromosome analysis and array comparative genomic hybridization (aCGH) showed duplications of overlapping regions at Xp21-p22. The duplicated segments contain numerous genes associated with MR, including AP1S2, NHS, CDKL5, RPS6KA3, SMS, and ARX. Except for developmental delay, there is little phenotypic overlap between the male and the female patient. Additionally, the female patient and affected female relatives of the male patient have variable severities of cognitive impairment, likely due to different X-inactivation patterns and effects of other, nonduplicated genes important for normal development. These cases illustrate that increased gene dosage of X-linked MR genes lead to cognitive impairment. Precise delineation of chromosome rearrangements by aCGH and identification of genes within duplicated segments helped in establishing genotype-phenotype correlations for each of our patients, in comparing them to each other, as well as with previously reported cases of Xp21-p22 duplications. However, we show that even with detailed molecular characterization, phenotype prediction remains challenging in patients with structural abnormalities of the X chromosome.
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PMID:Clinical and molecular characterization of overlapping interstitial Xp21-p22 duplications in two unrelated individuals. 2035

The ARX gene is involved in the development of GABAergic interneurons in the forebrain. Loss-of-function mutations, such as nonsense or frameshifts mutation, of ARX cause a group of brain malformations, such as hydranencephaly, lissencephaly, and agenesis of the corpus callosum, while expansion mutations of the polyalanine tracts of ARX, supposed to be gain-of-function mutations, result in a non-malformation group, such as non-syndromic mental retardation, mental retardation with dystonia, West syndrome, and Ohtahara syndrome. A variety of phenotypes caused by pleiotropic mutations of the ARX gene are considered to share a common pathological mechanism connected with the structural and functional disturbance of interneurons, designated as 'interneuronopathies'. We identified the second gene responsible for Ohtahara syndrome, STXBP1, which is essential for synaptic vesicle release. Molecular studies of the diseases will reveal the relationships between the structure and function of the brain. It is indispensable to clarify the etiology of hereditary diseases and identify new approaches to treatment.
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PMID:[Topics of brain malformation and epilepsy--age-dependent epileptic encephalopathies and interneuronopathies]. 2084 63

Mutations in the ARX gene cause both nonsyndromic and several forms of syndromic mental retardation (MR). Two polyalanine (polyA) expansions of ARX are recurrent mutations. The most common one, the c.428_451dup, is associated with a wide spectrum of phenotypes, ranging from the most severe West syndrome to Partington syndrome (MR and hand dystonia), and even nonsyndromic X-linked mental retardation (NS-XLMR). Studies of patients not selected for specific clinical signs showed that the c.428_451dup is relatively frequent in families harboring X-linked MR (7.5%), but less common in familial cases compatible with X-linked NR (1%), and very rare in sporadic cases (0.1%). The c.333_334ins(GCG)7 expansion is less frequent and mainly associated with West syndrome. We screened for both ARX polyA expansions in 98 unrelated patients selected for the presence of NR associated with different types of epilepsy and/or with hand dystonia. We also studied two families with an initial diagnosis of NS-XLMR, one of which was identified as showing linkage to the ARX locus. The c.428_451dup was identified in three patients and the c.333_334ins(GCG)7 in one; all of the patients were from families with two affected brothers. We also found the c.428_451dup in the family linked to ARX, and clinical re-evaluation showed subtle, previously undetected signs. Our study illustrates that ARX polyA expansions are primarily associated with syndromic MR and shows a higher yield (18% in our cohort) when these mutations are screened in familial cases of MR with epilepsy and/or dystonia.
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PMID:ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia. 2120 15

Genetic investigations of X-linked intellectual disabilities have implicated the ARX (Aristaless-related homeobox) gene in a wide spectrum of disorders extending from phenotypes characterised by severe neuronal migration defects such as lissencephaly, to mild or moderate forms of mental retardation without apparent brain abnormalities but with associated features of dystonia and epilepsy. Analysis of Arx spatio-temporal localisation profile in mouse revealed expression in telencephalic structures, mainly restricted to populations of GABAergic neurons at all stages of development. Furthermore, studies of the effects of ARX loss of function in humans and animal models revealed varying defects, suggesting multiple roles of this gene during brain development. However, to date, little is known about how ARX functions as a transcription factor and the nature of its targets. To better understand its role, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified a total of 1006 gene promoters bound by Arx in transfected neuroblastoma (N2a) cells and in mouse embryonic brain. Approximately 24% of Arx-bound genes were found to show expression changes following Arx overexpression or knock-down. Several of the Arx target genes we identified are known to be important for a variety of functions in brain development and some of them suggest new functions for Arx. Overall, these results identified multiple new candidate targets for Arx and should help to better understand the pathophysiological mechanisms of intellectual disability and epilepsy associated with ARX mutations.
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PMID:High-throughput analysis of promoter occupancy reveals new targets for Arx, a gene mutated in mental retardation and interneuronopathies. 2196 49

Mutations in the homeobox transcription factor ARX have been found to be responsible for a wide spectrum of disorders extending from phenotypes with severe neuronal migration defects, such as lissencephaly, to mild forms of intellectual disabilities without apparent brain abnormalities, but with associated features of dystonia and epilepsy. Arx expression is mainly restricted to populations of GABA-containing neurons. Studies of the effects of ARX loss of function, either in humans or mutant mice, revealed varying defects, suggesting multiple roles of this gene in brain patterning, neuronal proliferation and migration, cell maturation and differentiation, as well as axonal outgrowth and connectivity. However, to date, little is known about how Arx functions as a transcription factor or which genes it binds and regulates. Recently, we combined chromatin immunoprecipitation and mRNA expression with microarray analysis and identified approximately 1000 gene promoters bound by Arx in transfected neuroblastoma N2a cells and mouse embryonic brain. To narrow the analysis of Arx targets to those most likely to control cortical interneuron migration and/or differentiation, we compare here our data to previously published studies searching for genes enriched or down-regulated in cortical interneurons between E13.5 and E15.5. We thus identified 14 Arx-target genes enriched (Cxcr7, Meis1, Ppap2a, Slc 12a5, Ets2, Phlda1, Egr1, Igf1, Lmo3, Sema6, Lgi1, Alk, Tgfb3, and Napb) and 5 genes specifically down-regulated (Hmgn3, Lmo1, Ebf3, Rasgef1b, and Slit2) in cortical migrating neurons. In this review, we present these genes and discuss how their possible regulation by Arx may lead to the dysfunction of GABAergic neurons, resulting in mental retardation and epilepsy.
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PMID:Identification of Arx targets unveils new candidates for controlling cortical interneuron migration and differentiation. 2235 84

Mutations in the ARX gene, at Xp22.3, cause several disorders, including infantile spasms, X-linked lissencephaly with abnormal genitalia (XLAG), callosal agenesis and isolated intellectual disability. Genotype/phenotype studies suggested that polyalanine tract expansion is associated with non-malformative phenotypes, while missense and nonsense mutations cause cerebral malformations, however, patients with structural normal brain and missense mutations have been reported. We report on a male patient born with cleft lip and palate who presented with infantile spasms and hemiplegia. MRI showed agenesis of corpus callosum (ACC), an interhemispheric cyst, periventricular nodular heterotopia (PVNH), and extensive left frontal polymicrogyria (PMG). Sequencing of the ARX gene in the patient identified a six basepair insertion (c.335ins6, exon 2). The insertion leads to a two-residue expansion of the first polyalanine tract and was described previously in a family with non-syndromic X-linked mental retardation. To our knowledge, ARX mutation causing PMG and PVNH is unique, but the spasms and ACC are common in ARX mutations. Clinicians should be aware of the broad clinical range of ARX mutations, and further studies are necessary to investigate the association with PMG and PVNH and to identify possible modifying factors.
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PMID:Asymmetric polymicrogyria and periventricular nodular heterotopia due to mutation in ARX. 2258 66

ARX mutations give rise to both syndromic and nonsyndromic forms of mental retardation (MR). We investigated the most common ARX mutations, c.428_451 dup(24bp) and c.333ins (GCG)7 in a series of 370 mentally retarded FMR1 (CGG)n expansion mutation negative Turkish patients using PCR amplification and high resolution MetaPhor agarose gel electrophoresis. Sequence analysis was also performed for confirmation and discrimination of the mutations. One patient representing non-syndromic X-linked MR showed an abnormal band pattern on agarose gel and sequence analysis of exon 2 of the ARX gene revealed that the patient had the c.428_451 dup(24bp) mutation. When we screened the family members, we found that his sister and mother were also carrier for the same mutation. The proband showed mild MR and subtle clinical findings like dysarthria and lack of fine motor functions. In conclusion, the patients with weak fine motor skills and positive family history for X-linked MR should be screened for the most common ARX gene mutations.
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PMID:C.428_451 dup(24bp) mutation of the ARX gene detected in a Turkish family. 2307 84

Ten percent of cases of intellectual deficiency in boys are caused by genes located on the X chromosome. X-linked mental retardation (XLMR) includes more than 200 syndromes and 80 genes identified to date. The fragile X syndrome is the most frequent syndrome, due to a dynamic mutation with a CGG triplet amplification. Mental retardation is virtually always present. Phonological and syntactic impairments are often combined with pragmatic language impairment and visuospatial reasoning difficulties. A minority fulfill the criteria for autism. In girls, the clinical expression of the complete mutation varies according to the X chromosome inactivation profile. Several XLMR occur as severe early onset encephalopathies: Lowe oculocerebrorenal syndrome, ATR-X syndrome (alpha thalassemia/mental retardation X-linked), Allan-Herdon-Dudley syndrome (MCT8 gene). Two genes, ARX (X-LAG; Partington syndrome) and MECP2 (Rett syndrome in females; mild MR with spastic diplegia/psychotic problems in males) are associated with various phenotypes, according to the mutation involved. Oligophrenine 1 (OPHN-1) gene mutations lead to vermal dysplasia. PQBP1 gene mutations (Renpenning syndrome) are responsible for moderate to severe mental deficiency, microcephaly, and small stature. Although some forms of XLMR are not very specific and the phenotype for each given gene is somewhat heterogeneous, a clinical diagnostic strategy is emerging.
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PMID:X-linked mental deficiency. 2362 80

An elevated odds ratio for low IQ has been found for cryptorchid boys. Furthermore, poor school performance has been observed in cryptorchid boys with impaired mini-puberty. Gene expression analysis, qPCR and immunohistology were performed on testicular biopsies from 7 boys who underwent orchiopexy and had testicular histology typical of a high risk of infertility (HIR). The results were compared with 12 biopsies from cryptorchid boys with a low risk for developing infertility. The following genes associated with mental retardation were identically expressed: GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, ACSL4, MECP2, RPS6KA3, ARX, and ATRX. However, boys in the HIR group had low or no expression of EGR4, FMR2 (AFF2) and VCX3A. In conclusion, impaired expression of genes known to encode proteins involved in signaling pathways that regulate cytoskeletal organization, synaptic vesicle transport and the establishment of connections between neuronal cells may contribute to reduced intellectual and cognitive functioning in infertile cryptorchid males.
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PMID:Decreased expression of genes associated with memory and x-linked mental retardation in boys with non-syndromic cryptorchidism and high infertility risk. 2471 54

Mutations in the Aristaless related homeodomain transcription factor (ARX) are associated with a diverse set of X-linked mental retardation and epilepsy syndromes in humans. Although most studies have been focused on its function in the forebrain, ARX is also expressed in other regions of the developing nervous system including the floor plate (FP) of the spinal cord where its function is incompletely understood. To investigate the role of Arx in the FP, we performed gain-of-function studies in the chick using in ovo electroporation, and loss-of-function studies in Arx-deficient mice. We have found that Arx, in conjunction with FoxA2, directly induces Sonic hedgehog (Shh) expression through binding to a Shh floor plate enhancer (SFPE2). We also observed that FoxA2 induces Arx through its transcriptional activation domain whereas Nkx2.2, induced by Shh, abolishes this induction. Our data support a feedback loop model for Arx function; through interactions with FoxA2, Arx positively regulates Shh expression in the FP, and Shh signaling in turn activates Nkx2.2, which suppresses Arx expression. Furthermore, our data are evidence that Arx plays a role as a context dependent transcriptional activator, rather than a primary inducer of Shh expression, potentially explaining how mutations in ARX are associated with diverse, and often subtle, defects.
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PMID:Arx together with FoxA2, regulates Shh floor plate expression. 2496 61


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