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

Molecular defects affecting the ATRX gene lead to the ATRX syndrome (alpha thalassemia/mental retardation syndrome, X-linked), characterized by severe mental retardation, microcephaly, distinct facial dysmorphism, and genital abnormalities, as well as a wide spectrum of other pathological features. Alpha thalassemia is frequent but does not represent a constant characteristic of the syndrome. An expanding phenotype of the ATRX gene (a RAD54 homologue encoding a putative zinc-finger helicase) has been demonstrated as a result of the association of single mutations with specific X-linked mental retardation syndromes. To date, mutational analysis of the gene has been based on direct DNA sequencing or using methods with a lower detection rate. In this paper, we present a broad-range DGGE method for single-step mutation scanning of the entire open reading frame (ORF) and canonical splice sites of the gene. Using this method, we successfully identified five novel sequence changes in the ATRX gene, including four missense mutations (K1733E, R2085C, D2136N, T2169A) and one polymorphism (IVS5+35G>A).
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PMID:Mutational analysis of the ATRX gene by DGGE: a powerful diagnostic approach for the ATRX syndrome. 1267 95

ATRX syndrome is characterized by X-linked mental retardation associated with alpha-thalassemia. The gene mutated in this disease, ATRX, encodes a plant homeodomain-like finger and a SWI2/SNF2-like ATPase motif, both of which are often found in chromatin-remodeling enzymes, but ATRX has not been characterized biochemically. By immunoprecipitation from HeLa extract, we found that ATRX is in a complex with transcription cofactor Daxx. The following evidence supports that ATRX and Daxx are components of an ATP-dependent chromatin-remodeling complex: (i) Daxx and ATRX can be coimmunoisolated by antibodies specific for each protein; (ii) a proportion of Daxx cofractionates with ATRX as a complex of 1 MDa by gel-filtration analysis; (iii) in extract from cells of a patient with ATRX syndrome, the level of the Daxx-ATRX complex is correspondingly reduced; (iv) a proportion of ATRX and Daxx colocalize in promyelocytic leukemia nuclear bodies, with which Daxx had previously been located; and (v) the ATRX complex displays ATP-dependent activities that resemble those of other chromatin-remodeling complexes, including triple-helix DNA displacement and alteration of mononucleosome disruption patterns. But unlike the previously described SWI/SNF or NURD complexes, the ATRX complex does not randomize DNA phasing of the mononucleosomes, suggesting that it may remodel chromatin differently. Taken together, the results suggest that ATRX functions in conjunction with Daxx in a novel chromatin-remodeling complex. The defects in ATRX syndrome may result from inappropriate expression of genes controlled by this complex.
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PMID:The ATRX syndrome protein forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies. 1295 2

Mutations in the ATRX gene cause a severe X-linked mental retardation syndrome that is frequently associated with alpha thalassemia (ATR-X syndrome). The previously characterized ATRX protein (approximately 280 kDa) contains both a Plant homeodomain (PHD)-like zinc finger motif as well as an ATPase domain of the SNF2 family. These motifs suggest that ATRX may function as a regulator of gene expression, probably by exerting an effect on chromatin structure, although the exact cellular role of ATRX has not yet been fully elucidated. Here we characterize a truncated (approximately 200 kDa) isoform of ATRX (called here ATRXt) that has been highly conserved between mouse and human. In both species, ATRXt arises due to the failure to splice intron 11 from the primary transcript, and the use of a proximal intronic poly(A) signal. We show that the relative expression of the full length and ATRXt isoforms is subject to tissue-specific regulation. The ATRXt isoform contains the PHD-like domain but not the SWI/SNF-like motifs and is therefore unlikely to be functionally equivalent to the full length protein. We used indirect immunofluorescence to demonstrate that the full length and ATRXt isoforms are colocalized at blocks of pericentromeric heterochromatin but unlike full length ATRX, the truncated isoform does not associate with promyelocytic leukemia (PML) nuclear bodies. The high degree of conservation of ATRXt and the tight regulation of its expression relative to the full length protein suggest that this truncated isoform fulfills an important biological function.
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PMID:A conserved truncated isoform of the ATR-X syndrome protein lacking the SWI/SNF-homology domain. 1472 60

Death domain-associated protein (Daxx) is a multi-functional protein that modulates both apoptosis and transcription. Within the nucleus, Daxx is a component of the promyelocytic leukemia protein (PML) nuclear bodies (NBs) and interacts with a number of transcription factors, yet its precise role in transcription remains elusive. To further define the function of Daxx, we have isolated its interacting proteins in the nucleus using epitope-tagged affinity purification and identified X-linked mental retardation and alpha-thalassaemia syndrome protein (ATRX), a putative member of the SNF2 family of ATP-dependent chromatin remodeling proteins that is mutated in several X-linked mental retardation disorders. We show that substantial amounts of endogenous Daxx and ATRX exist in a nuclear complex. Daxx binds to ATRX through its paired amphipathic alpha helices domains. ATRX has ATPase activity that is stimulated by mononucleosomes, and patient mutations in the ATPase domain attenuate this activity. ATRX strongly represses transcription when tethered to a promoter. Daxx does not affect the ATPase activity of ATRX, however, it alleviates its transcription repression activity. In addition, ATRX is found in the PML-NBs, and this localization is mediated by Daxx. These results show that the ATRX.Daxx complex is a novel ATP-dependent chromatin-remodeling complex, with ATRX being the core ATPase subunit and Daxx being the targeting subunit. Moreover, the localization of ATRX to the PML-NBs supports the notion that these structures may play an important role in transcription regulation.
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PMID:A novel transcription regulatory complex containing death domain-associated protein and the ATR-X syndrome protein. 1499 May 86

The ATRX protein, associated with X-linked alpha-thalassaemia, mental retardation and developmental abnormalities including genital dysgenesis, has been proposed to function as a global transcriptional regulator within a multi-protein complex. However, an understanding of the composition and mechanics of this machinery has remained elusive. We applied inter-specific comparative analysis to identify conserved elements which may be involved in regulating the conformation of chromatin. As part of this study, we cloned and sequenced the entire translatable coding region (7.4 kb) of the ATRX gene from a model marsupial (tammar wallaby, Macropus eugenii). We identify an ATRX ancestral core, conserved between plants, fish and mammals, comprising the cysteine-rich and SWI2/SNF2 helicase-like regions and protein interaction domains. Our data are consistent with the model of the cysteine-rich region as a DNA-binding zinc finger adjacent to a protein-binding (plant homeodomain-like) domain. Alignment of vertebrate ATRX sequences highlights other conserved elements, including a negatively charged mammalian sequence which we propose to be involved in binding of positively charged histone tails.
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PMID:Comparative analysis of ATRX, a chromatin remodeling protein. 1536 44

In an ongoing study human X chromosomal mental retardation genes (MRX) were mapped in the chicken genome. Up to now the homologs of 13 genes were localized by FISH techniques. Four genes from HSAXp (TM4SF2, RSK2/RPS6KA3, NLGN4, ARX) map to GGA1q13-->q31, and seven genes from HSAXq (OPHN1, AGTR2, ARHGEF6, PAK3, FACL4/ACS4, FMR2, ATRX) to GGA4p. The gene-rich region of HSAXq28 proved to be much less conserved. GDI1 localized to GGA1pter and SLC6A8 to a mid-sized microchromosome. The order of the genes was determined from the newly available genome sequence data from chicken, which reveals exact colinearity between the genes in HSAXp and GGA1q13-->q31, but completely scrambled gene order between the genes with common synteny from HSAXq and GGA4p. This result supports the hypothesis that the human X chromosome is a real ancient autosomal linkage group.
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PMID:Localization of human X chromosomal mental retardation (MRX) genes in chicken and comparison with the chicken genome sequence data. 1562 55

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal "birthdating" confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.
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PMID:The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis. 1566 33

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X) is a syndromic form of X-linked mental retardation. We investigated the X-inactivation status of nine female ATR-X carriers by methylation-specific PCR of the HUMARA gene. Six carriers demonstrated a skewed X-inactivation pattern (>90:10) and one showed a non-skewed pattern (72:28), while two were uninformative because of homozygosity for the CAG repeat polymorphic alleles in the HUMARA. Only the carrier mother who showed non-skewed X-inactivation had moderate mental retardation. These findings suggest that mutations in ATRX may cause mental retardation in females, if the X chromosome carrying mutated ATRX is not properly inactivated.
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PMID:Non-skewed X-inactivation may cause mental retardation in a female carrier of X-linked alpha-thalassemia/mental retardation syndrome (ATR-X): X-inactivation study of nine female carriers of ATR-X. 1610 Jul 24

Mental retardation is more common in males than females in the population, assumed to be due to mutations on the X chromosome. The prevalence of the 24 genes identified to date is low and less common than expansions in FMR1, which cause Fragile X syndrome. Systematic screening of all other X linked genes in X linked families with mental retardation is currently not feasible in a clinical setting. The phenotypes of genes causing syndromic and non-syndromic mental retardation (NLGN3, NLGN4, RPS6KA3(RSK2), OPHN1, ATRX, SLC6A8, ARX, SYN1, AGTR2, MECP2, PQBP1, SMCX, and SLC16A2) are first discussed, as these may be the focus of more targeted mutation analysis. Secondly, the relative prevalence of genes causing only non-syndromic mental retardation (IL1RAPL1, TM4SF2, ZNF41, FTSJ1, DLG3, FACL4, PAK3, ARHGEF6, FMR2, and GDI) is summarised. Thirdly, the problem of recurrence risk where a molecular genetics diagnosis has not been made and what proportion of the male excess of mental retardation is due to monogenic disorders of the X chromosome are discussed.
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PMID:X linked mental retardation: a clinical guide. 1611 46

The alpha-thalassemia/mental retardation syndrome, X linked, also named ATR-X syndrome is a X-linked mental retardation syndrome. Mutations have been found in the ATRX gene in about one half of the patients. We report a typical clinical case. The clinical evidence leads us to continue the analysis of the gene despite a negative first screening. Indeed a new mutation was found, just behind the helicase domain, bringing up the interest of an effective collaboration between physicians and biologists.
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PMID:[ATR-X syndrome: a new mutation in the XNP/ATRX gene near the helicase domain]. 1612 58


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