共查询到20条相似文献,搜索用时 15 毫秒
1.
Tarpey P Parnau J Blow M Woffendin H Bignell G Cox C Cox J Davies H Edkins S Holden S Korny A Mallya U Moon J O'Meara S Parker A Stephens P Stevens C Teague J Donnelly A Mangelsdorf M Mulley J Partington M Turner G Stevenson R Schwartz C Young I Easton D Bobrow M Futreal PA Stratton MR Gecz J Wooster R Raymond FL 《American journal of human genetics》2004,75(2):318-324
We have identified truncating mutations in the human DLG3 (neuroendocrine dlg) gene in 4 of 329 families with moderate to severe X-linked mental retardation. DLG3 encodes synapse-associated protein 102 (SAP102), a member of the membrane-associated guanylate kinase protein family. Neuronal SAP102 is expressed during early brain development and is localized to the postsynaptic density of excitatory synapses. It is composed of three amino-terminal PDZ domains, an src homology domain, and a carboxyl-terminal guanylate kinase domain. The PDZ domains interact directly with the NR2 subunits of the NMDA glutamate receptor and with other proteins responsible for NMDA receptor localization, immobilization, and signaling. The mutations identified in this study all introduce premature stop codons within or before the third PDZ domain, and it is likely that this impairs the ability of SAP102 to interact with the NMDA receptor and/or other proteins involved in downstream NMDA receptor signaling pathways. NMDA receptors have been implicated in the induction of certain forms of synaptic plasticity, such as long-term potentiation and long-term depression, and these changes in synaptic efficacy have been proposed as neural mechanisms underlying memory and learning. The disruption of NMDA receptor targeting or signaling, as a result of the loss of SAP102, may lead to altered synaptic plasticity and may explain the intellectual impairment observed in individuals with DLG3 mutations. 相似文献
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Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation 下载免费PDF全文
Shoichet SA Hoffmann K Menzel C Trautmann U Moser B Hoeltzenbein M Echenne B Partington M Van Bokhoven H Moraine C Fryns JP Chelly J Rott HD Ropers HH Kalscheuer VM 《American journal of human genetics》2003,73(6):1341-1354
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Mutations in the FTSJ1 gene coding for a novel S-adenosylmethionine-binding protein cause nonsyndromic X-linked mental retardation 总被引:1,自引:0,他引:1 下载免费PDF全文
Freude K Hoffmann K Jensen LR Delatycki MB des Portes V Moser B Hamel B van Bokhoven H Moraine C Fryns JP Chelly J Gécz J Lenzner S Kalscheuer VM Ropers HH 《American journal of human genetics》2004,75(2):305-309
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C E Schwartz 《American journal of human genetics》1993,52(6):1025-1031
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Molinari F Foulquier F Tarpey PS Morelle W Boissel S Teague J Edkins S Futreal PA Stratton MR Turner G Matthijs G Gecz J Munnich A Colleaux L 《American journal of human genetics》2008,82(5):1150-1157
Mental retardation (MR) is the most frequent handicap among children and young adults. Although a large proportion of X-linked MR genes have been identified, only four genes responsible for autosomal-recessive nonsyndromic MR (AR-NSMR) have been described so far. Here, we report on two genes involved in autosomal-recessive and X-linked NSMR. First, autozygosity mapping in two sibs born to first-cousin French parents led to the identification of a region on 8p22-p23.1. This interval encompasses the gene N33/TUSC3 encoding one subunit of the oligosaccharyltransferase (OTase) complex, which catalyzes the transfer of an oligosaccharide chain on nascent proteins, the key step of N-glycosylation. Sequencing N33/TUSC3 identified a 1 bp insertion, c.787_788insC, resulting in a premature stop codon, p.N263fsX300, and leading to mRNA decay. Surprisingly, glycosylation analyses of patient fibroblasts showed normal N-glycan synthesis and transfer, suggesting that normal N-glycosylation observed in patient fibroblasts may be due to functional compensation. Subsequently, screening of the X-linked N33/TUSC3 paralog, the IAP gene, identified a missense mutation (c.932T-->G, p.V311G) in a family with X-linked NSMR. Recent studies of fucosylation and polysialic-acid modification of neuronal cell-adhesion glycoproteins have shown the critical role of glycosylation in synaptic plasticity. However, our data provide the first demonstration that a defect in N-glycosylation can result in NSMR. Together, our results demonstrate that fine regulation of OTase activity is essential for normal cognitive-function development, providing therefore further insights to understand the pathophysiological bases of MR. 相似文献
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Yonath H Marek-Yagel D Resnik-Wolf H Abu-Horvitz A Baris HN Shohat M Frydman M Pras E 《Journal of applied genetics》2011,52(4):437-441
The purpose of this study was to identify a gene causing non-syndromic X-linked mental retardation in an extended family, taking advantage of the X chromosome inactivation status of the females in order to determine their carrier state. X inactivation in the females was determined with the androgen receptor methylation assay; thereafter, the X chromosome was screened with evenly spaced polymorphic markers. Once initial linkage was identified, the region of interest was saturated with additional markers and the males were added to the analysis. Candidate genes were sequenced. Ten females showed skewed inactivation, while six revealed a normal inactivation pattern. A maximal lod score of 5.54 at θ?=?0.00 was obtained with the marker DXS10151. Recombination events mapped the disease gene to a 17.4-Mb interval between the markers DXS10153 and DXS10157. Three candidate genes in the region were sequenced and a previously described missense mutation (P375L) was identified in the ACSL4/FACL4 gene. On the basis of the female X inactivation status, we have mapped and identified the causative mutation in a gene causing non-syndromic X-linked mental retardation. 相似文献
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Bertani I Rusconi L Bolognese F Forlani G Conca B De Monte L Badaracco G Landsberger N Kilstrup-Nielsen C 《The Journal of biological chemistry》2006,281(42):32048-32056
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with Rett syndrome, West syndrome, and X-linked infantile spasms sharing the common features of generally intractable early seizures and mental retardation. Disease-causing mutations are distributed in both the catalytic domain and in the large COOH terminus. In this report, we examine the functional consequences of some Rett mutations of CDKL5 together with some synthetically designed derivatives useful to underline the functional domains of the protein. The mutated CDKL5 derivatives have been subjected to in vitro kinase assays and analyzed for phosphorylation of the TEY (Thr-Glu-Tyr) motif within the activation loop, their subcellular localization, and the capacity of CDKL5 to interact with itself. Whereas wild-type CDKL5 autophosphorylates and mediates the phosphorylation of the methyl-CpG-binding protein 2 (MeCP2) in vitro, Rett-mutated proteins show both impaired and increased catalytic activity suggesting that a tight regulation of CDKL5 is required for correct brain functions. Furthermore, we show that CDKL5 can self-associate and mediate the phosphorylation of its own TEY (Thr-Glu-Tyr) motif. Eventually, we show that the COOH terminus regulates CDKL5 properties; in particular, it negatively influences the catalytic activity and is required for its proper sub-nuclear localization. We propose a model in which CDKL5 phosphorylation is required for its entrance into the nucleus whereas a portion of the COOH-terminal domain is responsible for a stable residency in this cellular compartment probably through protein-protein interactions. 相似文献
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Ropers HH 《Current opinion in genetics & development》2006,16(3):260-269
X-linked mental retardation (XLMR) is a common cause of moderate to severe intellectual disability in males. XLMR is very heterogeneous, and about two-thirds of patients have clinically indistinguishable non-syndromic (NS-XLMR) forms, which has greatly hampered their molecular elucidation. A few years ago, international consortia overcame this impasse by collecting DNA and cell lines from large cohorts of XLMR families, thereby paving the way for the systematic study of the molecular causes of XLMR. Mutations in known genes might already account for 50% of the families with NS-XLMR, and various genes have been pinpointed that seem to be of particular diagnostic importance. Eventually, even therapy of XLMR might become possible, as suggested by the unexpected plasticity of the neuronal wiring in the brain, and the recent successful drug treatment of a fly model for fragile X syndrome. 相似文献
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Transcription factor SOX3 is involved in X-linked mental retardation with growth hormone deficiency 总被引:15,自引:0,他引:15 下载免费PDF全文
Laumonnier F Ronce N Hamel BC Thomas P Lespinasse J Raynaud M Paringaux C Van Bokhoven H Kalscheuer V Fryns JP Chelly J Moraine C Briault S 《American journal of human genetics》2002,71(6):1450-1455
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Dissociation between mental retardation and fragile site expression in a family with fragile X-linked mental retardation 总被引:2,自引:2,他引:0
M. A. Voelckel M. G. Mattei C. N'Guyen N. Philip F. Birg J. F. Mattei 《Human genetics》1988,80(4):375-378
Summary We report an extended family in which two brothers with a fragile X chromosome are mentally retarded while a third brother with the fragile site is both phenotypically and mentally normal. The study of six probes detecting restriction fragment length polymorphisms on either sides of the fragile site Xq27 confirmed that the fragile X regions inherited by these three brothers were identical from DXS 102 to the telomere. These data highlight the heterogeneity of the fragile X syndrome, which is discussed in the framework of the different hypotheses previously proposed. 相似文献
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Mutations in the BRWD3 gene cause X-linked mental retardation associated with macrocephaly 下载免费PDF全文
Field M Tarpey PS Smith R Edkins S O'Meara S Stevens C Tofts C Teague J Butler A Dicks E Barthorpe S Buck G Cole J Gray K Halliday K Hills K Jenkinson A Jones D Menzies A Mironenko T Perry J Raine K Richardson D Shepherd R Small A Varian J West S Widaa S Mallya U Wooster R Moon J Luo Y Hughes H Shaw M Friend KL Corbett M Turner G Partington M Mulley J Bobrow M Schwartz C Stevenson R Gecz J Stratton MR Futreal PA Raymond FL 《American journal of human genetics》2007,81(2):367-374
In the course of systematic screening of the X-chromosome coding sequences in 250 families with nonsyndromic X-linked mental retardation (XLMR), two families were identified with truncating mutations in BRWD3, a gene encoding a bromodomain and WD-repeat domain–containing protein. In both families, the mutation segregates with the phenotype in affected males. Affected males have macrocephaly with a prominent forehead, large cupped ears, and mild-to-moderate intellectual disability. No truncating variants were found in 520 control X chromosomes. BRWD3 is therefore a new gene implicated in the etiology of XLMR associated with macrocephaly and may cause disease by altering intracellular signaling pathways affecting cellular proliferation. 相似文献
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A new form of X-linked mental retardation with growth retardation, deafness, and microgenitalism. 总被引:4,自引:3,他引:1 下载免费PDF全文
The proband and two maternal uncles were similarly affected by a unique constellation of mental retardation and physical abnormalities. There were severe retardation, growth less than the third percentile, and significantly delayed bone age. They manifested deafness, a flat nasal bridge, several ocular abnormalities, and a rudimentary scrotum with cryptorchidism, and one had a small penis. The proband also had onychodystrophy of his fingers and toes. Their birth weights and lengths were less than expected. No chromosomal or biochemical abnormality was detected. Both uncles died, but the proband is healthy at 4 years. Their phenotype is distinguished from other forms of X-linked mental retardation and appears to be a new syndrome. 相似文献
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H Malmgren M Sundvall N Dahl K H Gustavson G Annern C Wadelius M L Sten-Bondeson U Pettersson 《American journal of human genetics》1993,52(6):1046-1052
A four-generation Swedish family with a new type of X-linked mental retardation syndrome was recently reported by Gustavson et al. The complex syndrome includes microcephaly, severe mental retardation, optical atrophy with decreased vision or blindness, severe hearing defect, characteristic facial features, spasticity, seizures, and restricted joint motility. The patients die during infancy or early in childhood. Twenty-one family members, including two affected males, were available for study. Linkage analysis was conducted in the family by using 11 RFLP markers and 10 VNTR markers spread along the X chromosome. A hypervariable short tandem repeat of DXS294 at Xq26 showed a peak two-point lod score of 3.35 at zero recombination fraction. Calculations using the same markers revealed a multipoint peak lod score of 3.65 at DXS294. Crossover events with the centromeric marker DXS424 and the telomeric marker DXS297 delimit a probable region for the gene localization. It is noteworthy that hte disease loci of two other syndromes with overlapping clinical manifestations recently were shown by Turner et al. and Pettigrew et al. to be linked to markers at Xq26. 相似文献
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Stephen T. Warren Thomas W. Glover Richard L. Davidson Pudur Jagadeeswaran 《Human genetics》1985,69(1):44-46
Summary Linkage analysis on a family with fragile X-linked mental retardation was performed using a Taq 1 restriction fragment length polymorphism detected by a cloned human coagulation factor IX cDNA. Two affected brothers in this sibship were found to have different factor IX RFLP alleles, indicating a recombinational event occurred between the two genes. Our data therefore indicate that the gene responsible for fragile X-linked mental retardation is not as tightly linked to the factor IX gene as the previously published data may suggest. 相似文献
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Hagens O Dubos A Abidi F Barbi G Van Zutven L Hoeltzenbein M Tommerup N Moraine C Fryns JP Chelly J van Bokhoven H Gécz J Dollfus H Ropers HH Schwartz CE de Cassia Stocco Dos Santos R Kalscheuer V Hanauer A 《Human genetics》2006,118(5):578-590
The extensive heterogeneity underlying the genetic component of mental retardation (MR) is the main cause for our limited
understanding of the aetiology of this highly prevalent condition. Hence we set out to identify genes involved in MR. We investigated
the breakpoints of two balanced X;autosome translocations in two unrelated female patients with mild/moderate MR and found
that the Xp11.2 breakpoints disrupt the novel human KIAA1202 (hKIAA1202) gene in both cases. We also identified a missense exchange in this gene, segregating with the Stocco dos Santos XLMR syndrome
in a large four-generation pedigree but absent in >1,000 control X-chromosomes. Among other phenotypic characteristics, the
affected males in this family present with severe MR, delayed or no speech, seizures and hyperactivity. Molecular studies
of hKIAA1202 determined its genomic organisation, its expression throughout the brain and the regulation of expression of its mouse homologue
during development. Transient expression of the wild-type KIAA1202 protein in HeLa cells showed partial colocalisation with
the F-actin based cytoskeleton. On the basis of its domain structure, we argue that hKIAA1202 is a new member of the APX/Shroom
protein family. Members of this family contain a PDZ and two ASD domains of unknown function and have been shown to localise
at the cytoskeleton, and play a role in neurulation, cellular architecture, actin remodelling and ion channel function. Our
results suggest that hKIAA1202 may be important in cognitive function and/or development.
Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.
O. Hagens and A. Dubos contributed equally to this work. 相似文献