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)

Nonsyndromic X-linked mental retardation (MRX) is defined by an X-linked inheritance pattern of low IQ, problems with adaptive behavior, and the absence of additional specific clinical features. The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families. In a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21), we have cloned the DNA fragment that contains the X-chromosomal and the autosomal breakpoint. In silico sequence analysis provided no indication of a causative role for the chromosome 7 breakpoint in mental retardation (MR), whereas, on the X chromosome, a zinc-finger gene, ZNF41, was found to be disrupted. Expression studies indicated that ZNF41 transcripts are absent in the patient cell line, suggesting that the mental disorder in this patient results from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals. A proline-to-leucine amino acid exchange is present in affected members of one family with MRX. A second family carries an intronic splice-site mutation that results in loss of specific ZNF41 splice variants. Wild-type ZNF41 contains a highly conserved transcriptional repressor domain that is linked to mechanisms of chromatin remodeling, a process that is defective in various other forms of MR. Our results suggest that ZNF41 is critical for cognitive development; further studies aim to elucidate the specific mechanisms by which ZNF41 alterations lead to MR.
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PMID:Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. 1462 91

We found mutations in the gene PQBP1 in 5 of 29 families with nonsyndromic (MRX) and syndromic (MRXS) forms of X-linked mental retardation (XLMR). Clinical features in affected males include mental retardation, microcephaly, short stature, spastic paraplegia and midline defects. PQBP1 has previously been implicated in the pathogenesis of polyglutamine expansion diseases. Our findings link this gene to XLMR and shed more light on the pathogenesis of this common disorder.
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PMID:Mutations in the polyglutamine binding protein 1 gene cause X-linked mental retardation. 1463 49

The X chromosomal mental retardation genes have attained high interest in the past. A rough classification distinguishes syndromal mental retardation (MRXS) and nonsyndromal mental retardation (MRX) conditions. The latter are suggested to be responsible for human specific development of cognitive abilities. These genes have been shown to be engaged in chromatin remodelling or in intracellular signalling. During this analysis, we have compared the expression pattern in the mouse of four genes from the latter class of MRX genes: Ophn1, Arhgef6 (also called alphaPix), Pak3, and Gdi1. Ophn1, Pak3, and Gdi1 show a specific neuronal expression pattern with a certain overlap that allows to assign these signalling molecules to the same functional context. We noticed the highest expression of these genes in the dentate gyrus and cornu ammonis of the hippocampus, in structures engaged in learning and memory. A completely different expression pattern was observed for Arhgef6. In the CNS, it is expressed in ventricular zones, where neuronal progenitor cells are located. But Arhgef6 expression is also found in other non-neural tissues. Our analysis provides evidence that these signalling molecules are involved in different spatio-temporal expression domains of common signalling cascades and that for most tissues considerable functional redundancy of Rho-mediated signalling pathways exists.
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PMID:A comparative expression analysis of four MRX genes regulating intracellular signalling via small GTPases. 1467 71

Of 11 genes involved in nonspecific X-linked mental retardation (MRX), three encode regulators or effectors of the Rho GTPases, suggesting an important role for Rho signaling in cognitive function. It remains unknown, however, how mutations in Rho-linked genes lead to MRX. Here we report that oligophrenin-1, a Rho-GTPase activating protein that is absent in a family affected with MRX, is required for dendritic spine morphogenesis. Using RNA interference and antisense RNA approaches, we show that knock-down of oligophrenin-1 levels in CA1 neurons in rat hippocampal slices significantly decreases spine length. This phenotype can be recapitulated using an activated form of RhoA and rescued by inhibiting Rho-kinase, indicating that reduced oligophrenin-1 levels affect spine length by increasing RhoA and Rho-kinase activities. We further demonstrate an interaction between oligophrenin-1 and the postsynaptic adaptor protein Homer. Our findings provide the first insight into how mutations in a Rho-linked MRX gene may compromise neuronal function.
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PMID:The X-linked mental retardation protein oligophrenin-1 is required for dendritic spine morphogenesis. 1503 83

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

X-linked mental retardation (XLMR) is a heterogenous set of conditions responsible for a large proportion of inherited mental retardation. Approximately 200 XLMR conditions and 45 cloned genes are now listed in our catalogue on the Internet at http://xlmr.interfree.it/home.htm. Traditionally, XLMR conditions were subdivided into specific (MRXS) and nonspecific (MRX) forms, depending on their clinical presentation. Now that a growing number of candidate genes have become available for screening XLMR families and patients, this distinction is becoming less useful and similar conditions that had been previously listed as separate can now be grouped together because different mutations in the same gene have been identified. Furthermore, different mutations in the same XLMR gene may account for diseases of increasing severity, but can also cause different phenotypes. As the functions of proteins corresponding to these genes are characterized, biological networks involved in causing mental retardation and conversely in supporting normal intellectual functioning will be discovered. Molecular biologists and neurobiologists will need to cooperate in order to verify the effects of XLMR gene mutations in the context of neuronal circuitry. Eventually, DNA and protein microarray technologies will assist researchers and physicians in reaching a diagnosis even in small families or in individual patients with XLMR.
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PMID:X-linked mental retardation (XLMR): from clinical conditions to cloned genes. 1527 May 52

By using several microsatellite markers scattered along the X chromosome, we studied a Chinese family with nonspecific X-linked mental retardation (MRX84) to search for a region including the MRX84 locus that was linked to the markers. Two-point linkage analysis demonstrated linkage between the disorder and several markers located at Xq22.2, with maximum LOD score Z(max) = 2.41 at recombination fraction theta = 0 for DXS1191 and DXS1230, respectively. Recombination events were observed with flanking markers DXS8080 and DXS456, located at Xp11.3 and Xq22.3, respectively, and a region of approximately 22.3 cM was defined. Accordingly, markers distal to Xp11.3 and Xq22.3 segregated independently of the disease. The localized region observed in this Chinese family overlaps with 29 other MRX loci previously reported in Xp11.3-q22.3. These results should contribute to the identification of the disease gene for the MRX84 disorder.
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PMID:A locus for nonspecific X-linked mental retardation mapped to a 22.3 cM region of Xp11.3-q22.3. 1532 29

Clinical and molecular studies are reported on a Basque family (MRX82) with nonsyndromic X-linked mental retardation (XLMR) in five affected males. A total of 38 microsatellite markers were typed. The XLMR locus has been linked to DXS8067, DXS1001, DXS425, DXS7877, and DXS1183 with a maximum LOD score of 2.4. The haplotype studies and multipoint linkage analysis suggest a localization of the MRX82 locus to an interval of 7.6 Mb defined by markers DXS6805 and DXS7346, in Xq24 and Xq25, respectively. No gene contained in this interval has been so far associated with nonsyndromic mental retardation, except for GRIA3, disrupted by a balanced translocation in a female patient with bipolar affective disorder and mental retardation. However, the search for mutations of this gene did not showed a pathogenic mutation in the present family. Given that there are other eight MRX families overlapping this interval, none of them with known mutation, we conclude that at least one new gene responsible for nonsyndromic mental retardation is located in this region.
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PMID:Localization of MRX82: a new nonsyndromic X-linked mental retardation locus to Xq24-q25 in a Basque family. 1552 94

Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit. The mechanisms through which PAK3 mutation produces the mental handicap remain unclear, although an involvement in the mechanisms that regulate the formation or plasticity of synaptic networks has been proposed. Here we show, using a transient transfection approach, that antisense and small interfering RNA-mediated suppression of PAK3 or expression of a dominant-negative PAK3 carrying the human MRX30 mutation in rat hippocampal organotypic slice cultures results in the formation of abnormally elongated dendritic spines and filopodia-like protrusions and a decrease in mature spine synapses. Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals. These defects are associated with a reduced spontaneous activity, altered expression of AMPA-type glutamate receptors, and defective long-term potentiation. Together, these data identify PAK3 as a key regulator of synapse formation and plasticity in the hippocampus and support interpretations that these defects might contribute to the cognitive deficits underlying this form of mental retardation.
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PMID:The mental retardation protein PAK3 contributes to synapse formation and plasticity in hippocampus. 1557 32

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


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