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

The ATR-X syndrome is an X-linked disorder comprising severe psychomotor retardation, characteristic facial features, genital abnormalities, and alpha-thalassemia. We have shown that ATR-X results from diverse mutations of XH2, a member of a subgroup of the helicase superfamily that includes proteins involved in a wide range of cellular functions, including DNA recombination and repair (RAD16, RAD54, and ERCC6) and regulation of transcription (SW12/SNF2, MOT1, and brahma). The complex ATR-X phenotype suggests that XH2, when mutated, down-regulates expression of several genes, including the alpha-globin genes, indicating that it could be a global transcriptional regulator. In addition to its role in the ATR-X syndrome, XH2 may be a good candidate for other forms of X-linked mental retardation mapping to Xq13.
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PMID:Mutations in a putative global transcriptional regulator cause X-linked mental retardation with alpha-thalassemia (ATR-X syndrome). 769 14

Several human inherited diseases have been localized to the Xq13.3 region of the human X chromosome (X-linked dystonia with Parkinsonism, sideroblastic anemia, SCID, Menkes disease and X-linked mental retardation loci). Genes involved in the phenotypes have been isolated for only two of them (Menkes and SCIDX). It was therefore interesting to isolate and characterize new genes from the region. In a previous work (12 and Consalez et al, in preparation) we isolated a gene (XNP), located 350 Kb proximal to PGK1, potentially coding for a nuclear protein. We describe here the cloning and characterization of the murine homologue. The pattern of expression of the gene in the newborn mouse (especially the expression in particular regions of the brain: optical lobe, frontal cortex, hippocampus and cerebellum), as well as the expression in human tissues, suggests that this gene might be involved in neuronal differentiation. Among the different morbid phenotypes assigned to the region, X-linked mental retardation would be the best candidate to be associated with this gene.
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PMID:Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3. 816 50

Mental handicap is a common clinical problem that has been a relatively neglected area of research. Though the causes are varied and complex, molecular biologists are making progress in understanding the mechanisms in some cases, particularly where there are distinguishing phenotypic or genetic markers. The fortuitous association of alpha thalassaemia with a form of mental retardation has allowed us to define a specific X-linked syndrome (ATR-X). Positional cloning was used to define a disease interval and examination of candidate genes demonstrated that mutations in a gene, XH2, showing homology to the SNF2 superfamily were responsible for this syndrome. The complex ATR-X phenotype suggests that this gene, when mutated, down-regulates the expression of several genes including the alpha-globin genes indicating that it could be a global transcriptional regulator. It is conceivable that this mechanism is involved in other forms of syndromal mental retardation.
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PMID:Syndromal mental retardation due to mutations in a regulator of gene expression. 854 68

The chromosome-16 and the X-chromosome forms of alpha-thalassemia--ATR-16 and ATR-X--exemplify 2 important causes of syndromal mental retardation. ATR-16 is a contiguous gene syndrome which arises from loss of DNA from the tip of chromosome 16p13.3 by truncation, interstitial deletion, or unbalanced translocation. It provided the first example of a chromosome translocation that could be detected by molecular analysis but not conventional cytogenetics. It also provided the first example of a telomeric truncation giving rise to a complex genetic syndrome. In contrast ATR-X appears to be due to mutations in a trans-acting factor that regulates gene expression. Mutations in transcription factors have recently been identified in a number of genetic diseases (for example, Denys-Drash syndrome, WT1 [19]; pituitary dwarfism, PIT1 [16]; Rubinstein-Taybi syndrome, CBP [20]. Not only is this mechanism proving to be an important cause of complex syndromes but it is providing new perspectives on certain developmental pathways. XH2 may not be a classical transcription factor but it is certainly involved in the regulation of gene expression, exerting its effects on several different genes. It seems likely that other mutations in this class of regulatory proteins will be found in patients with complex disorders including mental retardation. In broader terms the 2 mechanisms described here may prove to be responsible for a significant proportion of mental retardation. However, without a feature such as alpha-thalassemia to pinpoint the area of genome or pathways involved it may prove difficult to identify other, similarly affected genes underlying other forms of mental retardation. As the human genome project and rapid genome analysis evolve this problem should become less of an obstacle. In the meantime, it is very worthwhile to continue looking for unusual clinical associations that may point to critical genes underlying human genetic disorders.
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PMID:The alpha-thalassemia/mental retardation syndromes. 860 26

We have previously reported the isolation of a gene from Xq13 that codes for a putative regulator of transcription (XNP) and has now been shown to be the gene involved in the X-linked alpha-thalassemia with mental retardation (ATR-X) syndrome. The widespread expression and numerous domains present in the putative protein suggest that this gene could be involved in other phenotypes. The predominant expression of the gene in the developing brain, as well as its association with neuron differentiation, indicates that mutations of this gene might result in a mental retardation (MR) phenotype. In this paper we present a family with a splice junction mutation in XNP that results in the skipping of an exon and in the introduction of a stop codon in the middle of the XNP-coding sequence. Only the abnormal transcript is expressed in two first cousins presenting the classic ATR-X phenotype (with alpha-thalassemia and HbH inclusions). In a distant cousin presenting a similar dysmorphic MR phenotype but not having thalassemia, approximately 30% of the XNP transcripts are normal. These data demonstrate that the mode of action of the XNP gene product on globin expression is distinct from its mode of action in brain development and facial morphogenesis and suggest that other dysmorphic mental retardation phenotypes, such as Juberg-Marsidi or some sporadic cases of Coffin-Lowry, could be due to mutations in XNP.
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PMID:Splicing mutation in the ATR-X gene can lead to a dysmorphic mental retardation phenotype without alpha-thalassemia. 864 9

We describe a pedigree presenting X-linked severe mental retardation associated with multiple congenital abnormalities and 46,XY gonadal dysgenesis, leading in one family member to female gender assignment. Female carriers are unaffected. The dysmorphic features are similar to those described in the alpha-thalassemia and mental retardation (ATR-X) syndrome, although there is no clinical evidence of alpha-thalassemia in this family. In addition, the family had other clinical features not previously observed in the ATR-X syndrome, including partial optic-nerve atrophy and partial ocular albinism. Mutations in a putative DNA helicase, termed XH2, have been reported to give rise to the ATR-X syndrome. We screened the XH2 gene for mutations in affected members of the family and identified a 4-bp deletion at an intron/exon boundary that removes an invariant 3' splice-acceptor site. The mutation cosegregates with the syndrome. The genomic deletion causes missplicing of the pre-mRNA, which results in the loss of 8 bp of coding sequence, thereby generating a frameshift and a downstream premature stop codon. Our finding increases the range of clinical features associated with mutations in the XH2 gene.
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PMID:A novel mutation in the putative DNA helicase XH2 is responsible for male-to-female sex reversal associated with an atypical form of the ATR-X syndrome. 865 Dec 95

We have previously reported the isolation of a gene from Xq13, coding for a putative regulator of transcription (XNP). It is a member of the helicase family, and has now been shown to be the gene involved in the X-linked alpha-thalassemia/mental retardation (ATR-X) syndrome. ATR-X mutations were only found in the 3'-part of the coding sequence, which includes the helicase domains. However, no ATR-X mutation has yet been found in one of the seven conserved helicase domains. In this paper, we report a mutation in XNP, segregating in a family presenting an "ATR-X' phenotype without alpha-thalassemia, that causes a proline to serine transition in the helicase II domain.
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PMID:A point mutation in the XNP gene, associated with an ATR-X phenotype without alpha-thalassemia. 904 63

The XNP/ATR-X gene is involved in several X-linked mental retardation phenotypes: the ATR-X syndrome, the Juberg-Marsidi syndrome, and some severe mental retardation phenotypes without alpha-thalassemia. Using a vectorette strategy, we have identified and sequenced the intron/exon boundaries of this gene. The gene is composed of 35 exons. It encodes a potential protein of 2492 amino acids. A search of the databases identified three zinc finger motifs within the 5' end of the gene. Expression analysis in different tissues indicated that an alternative splicing event that involves exon 6 is occurring. One of these alternatively spliced transcripts is predominantly expressed in embryonic tissues. These data led us to search for mutations in the 5' region in ATRX patients without other mutations in the 3' region. In one patient a mutation was found in which part of exon 7 was removed from the XNP transcript, as a result of a mutation creating a novel splice site that is substituted for the natural splice site. This new splicing event removed one zinc finger motif. This is the first example of a mutation in XNP within the 5' coding region. It suggests that mutations will be predominantly found in the helicase region as well as in the zinc finger regions and leads us to propose a large screening of additional patients.
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PMID:Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase. 924 31

Mutations in the XNP gene result in different inherited disorders, including the ATR-X syndrome which is characterized by mental retardation (MR) associated with alpha-thalaessemia. Amino acid sequence analysis revealed that the XNP protein is a new member of the SNF2-like family, which comprises numerous members involved in a broad range of biological functions: transcriptional regulation, DNA repair and chromosome segregation. Since experiments on fibroblasts from ATR-X patients have provided no evidence for either a DNA repair defect or abnormal chromosome breakage or segregation, it seems more likely that the XNP protein is somehow involved in regulation of gene expression. Recent genetic and biochemical studies have led to the emerging concept that SNF2-like proteins are components of a large protein complex which may exert its functions by modulating chromatin structure. To investigate whether XNP could mediate the activity of gene-specific activators through chromatin remodelling, we performed a yeast two-hybrid analysis using XNP and several human heterochromatin-associated proteins. We found a specific interaction between the XNP and the EZH2 proteins. In light of these observations, we discuss how the XNP protein may regulate gene transcription at the chromatin level.
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PMID:Specific interaction between the XNP/ATR-X gene product and the SET domain of the human EZH2 protein. 949 21

We report on the evaluation of a strategy for screening for XNP/ATR-X mutations in males with mental retardation and associated dysmorphology. Because nearly half of the mutations in this gene reported to date fall into a short 300 bp region of the transcript, we decided to focus in this region and to extend the mutation analysis to cases with a negative family history. This study includes 21 mentally retarded male patients selected because they had severe mental retardation and a typical facial appearance. The presence of haemoglobin H or urogenital abnormalities was not considered critical for inclusion in this study. We have identified six mutations which represents a mutation detection rate of 28%. This figure is high enough for us to propose this strategy as a valid first level of screening in a selected subset of males with mental retardation. This approach is simple, does not require RNA preparation, does not involve time consuming mutation detection methods, and can thus be applied to a large number of patients at a low cost in any given laboratory.
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PMID:Evaluation of a mutation screening strategy for sporadic cases of ATR-X syndrome. 1020 41


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