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)

Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.
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PMID:A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer. 1567 31

Molecular cytogenetics allows the identification of cryptic chromosome rearrangements, which is clinically useful in mentally retarded and/or dysmorphic individuals with normal results from conventional cytogenetics analysis. We report on a 3-year-old girl with mental retardation, growth deficiency, speech delay, and dysmorphic features including hypertelorism, upslanting palpebral fissures, midfacial hypoplasia, and posteriorly rotated ears. The G-banding analysis showed a 46,XX,t(3;8)(q26.2;p21.1)mat karyotype. However, her clinical features were suggestive of the 18q syndrome. Subtelomeric FISH analysis revealed a der(18) translocated material from chromosome 17. Array-based comparative genomic hybridization (array-CGH) with subtelomeric BAC and PAC clones confirmed the abnormality and refined the breakpoints to 18q22.3-qter and 17p13.2-pter (deletion of 8.5 Mb and duplication of 3.9 Mb, respectively). This case demonstrates the diagnostic utility of combining conventional cytogenetics with molecular chromosome analyses for the identification of subtle chromosome abnormalities.
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PMID:Cryptic unbalanced translocation t(17;18)(p13.2;q22.3) identified by subtelomeric FISH and defined by array-based comparative genomic hybridization in a patient with mental retardation and dysmorphic features. 1601 83

X-linked mental retardation (XLMR) is a heterogeneous disorder that can be classified as either non-specific (MRX), when mental retardation is the only feature, or as syndromic mental retardation (MRXS). Genetic defects underlying XLMR are being identified at a rapid pace, often starting from X-chromosomal aberrations and XLMR families with a well-defined linkage interval. Here, we present a new family with a syndromic form of XLMR, including mild mental retardation, short stature, microcephaly and hypogonadism. Two-point linkage analysis with 24 polymorphic markers spanning the entire X chromosome was carried out. We could assign the causative gene to a 6 cM interval in Xp22.1-p21.3, with a maximum LOD score of 2.61 for markers DXS989 and DXS1061 at theta = 0.00. No mutations were found in the presented family for two known MRX genes mapping to this interval, ARX and IL1RAPL-1. These data indicate that the interval Xp22.1-p21.3 contains at least one additional MRXS gene.
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PMID:X-linked mental retardation, short stature, microcephaly and hypogonadism maps to Xp22.1-p21.3 in a Belgian family. 1605 5

Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.
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PMID:Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. 1641 66

The Cool (Cloned out of Library)/Pix (Pak interactive exchange factor) proteins have been implicated in a diversity of biological activities, ranging from pathways initiated by growth factors and chemoattractants to X-linked mental retardation. Initially discovered through yeast two-hybrid and biochemical analyses as binding partners for the Cdc42/Rac-target/effector, Pak (p21 activated kinase), the sequences for the Cool/Pix proteins revealed a DH (Dbl homology) domain. Because the DH domain is the limit functional unit for stimulating guanine nucleotide exchange on Rho family GTP-binding proteins, it was assumed that the Cool/Pix proteins would act as guanine nucleotide exchange factors (GEFs) for the Rho proteins. Of the three known isoforms, (p50Cool-1, p85Cool-1/beta-Pix, and 90Cool-2/alpha-Pix), only Cool-2/alpha-Pix has exhibited significant GEF activity. A number of experimental techniques have been used to characterize Cool-2, and in vitro analysis has revealed that its GEF activity is under tight control through intramolecular interactions involving several binding partners. Here we describe the biochemical methods used to study the Cool/Pix proteins and, in particular, the regulation of the GEF activity of Cool-2/alpha-Pix.
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PMID:Biochemical characterization of the Cool (Cloned-out-of-Library)/Pix (Pak-interactive exchange factor) proteins. 1647 49

The loss of p53 function is a key event in tumorigenesis. Inactivation of p53 in primary tumors and cell lines is mediated by several molecular mechanisms, including deletions and rearrangements. However, generation of a p53 fusion gene has not yet been reported. Here we report a novel p53/an autosomal homolog of the fragile X mental retardation (FXR2) chimeric gene generated by an interstitial deletion. Western blot analyses have shown that the p53/FXR2 protein is indeed expressed in a Down syndrome-related acute megakaryoblastic leukemia cell line, CMK11-5 cells. To investigate the properties of the p53/FXR2 protein, we observed its subcellular localization. Flag-tagged expression vectors were transfected into COS-7 cells and the proteins were stained with an anti-Flag antibody. The p53/FXR2 protein was expressed at high levels in the cytoplasm, whereas wild-type p53 and FXR2 were localized primarily in the nucleus and in the periphery of the nucleus, respectively. Treatment with a topoisomerase II inhibitor, VP16, failed to induce expression of a p53 target gene, the cyclin-dependent kinase inhibitor p21(WAF-1/CIP1), in CMK11-5 cells, and transient transfection analysis showed that the p53/FXR2 protein failed to transactivate the p21(WAF-1/CIP1) promoter. These results suggest that the p53/FXR2 fusion protein lacks the ability of wild-type p53 to function as a transcription factor. The p53/FXR2 gene is the first reported p53 fusion gene.
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PMID:Cloning and characterization of the novel chimeric gene p53/FXR2 in the acute megakaryoblastic leukemia cell line CMK11-5. 1677 63

Gene mapping data indicate that the human X chromosome is enriched in genes that affect both, higher cognitive efficiency and reproductive success. This raises the question whether these functions are ancient, or whether conserved X-linked genes were recruited to new functions. We have studied three X-linked mental retardation (XLMR) genes by RNA in situ hybridization in mouse and in chicken, in which these genes are autosomal: Rho guanine nucleotide exchange factor 6 (ARHGEF6), oligophrenin (OPHN1), and p21 activated kinase 3 (PAK3). In the mouse these genes are specifically expressed in telencephalic regions. Their orthologues in the chicken gave patterns of similar specificity in ancient parts of the brain, i.e. cerebellum and mesencephalon, but were not expressed in the telencephalon. Also in the testes, specific expression was only found in mouse, not in chicken. These data are interpreted such that certain genes on the X chromosome gained novel functions during evolution.
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PMID:Recruitment of old genes to new functions: evidences obtained by comparing the orthologues of human XLMR genes in mouse and chicken. 1731 56

Fragile X syndrome (FXS), the most commonly inherited form of mental retardation and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene and consequent loss of the fragile X mental retardation protein. Despite growing evidence suggesting a role of specific receptors and biochemical pathways in FXS pathogenesis, an effective therapeutic method has not been developed. Here, we report that abnormalities in FMR1 knockout (KO) mice, an animal model of FXS, are ameliorated, at least partially, at both cellular and behavioral levels, by an inhibition of the catalytic activity of p21-activated kinase (PAK), a kinase known to play a critical role in actin polymerization and dendritic spine morphogenesis. Greater spine density and elongated spines in the cortex, morphological synaptic abnormalities commonly observed in FXS, are at least partially restored by postnatal expression of a dominant negative (dn) PAK transgene in the forebrain. Likewise, the deficit in cortical long-term potentiation observed in FMR1 KO mice is fully restored by the dnPAK transgene. Several behavioral abnormalities associated with FMR1 KO mice, including those in locomotor activity, stereotypy, anxiety, and trace fear conditioning are also ameliorated, partially or fully, by the dnPAK transgene. Finally, we demonstrate a direct interaction between PAK and fragile X mental retardation protein in vitro. Overall, our results demonstrate the genetic rescue of phenotypes in a FXS mouse model and suggest that the PAK signaling pathway, including the catalytic activity of PAK, is a novel intervention site for development of an FXS and autism therapy.
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PMID:Inhibition of p21-activated kinase rescues symptoms of fragile X syndrome in mice. 1759 39

Complex chromosome rearrangements (CCRs) are rare structural abnormalities that involve at least two chromosomes and more than two breakpoints and are often associated with developmental delay, mental retardation, and congenital anomalies. We report on a de novo, apparently balanced translocation t(1;5;7)(p32.1;q14.3;p21.3) involving three chromosomes in a 7-year-old boy with severe psychomotor retardation, neonatal muscular hypertonia, congenital heart defect, polysyndactyly of hands and feet, and dysmorphic features resembling Greig cephalopolysyndactyly syndrome. Analysis of the chromosome breakpoints using fluorescence in situ hybridization (FISH) with locus-specific BAC clones and long-range PCR products did not identify chromosome imbalance at any of the interrogated regions. High-resolution comparative genomic hybridization (HR-CGH) and array CGH (aCGH) revealed two additional cryptic de novo deletions, del(1)(p31.1p31.1) and del(7)(p14.1p14.1), respectively, that are not associated with the translocation breakpoints. FISH and polymorphic marker analyses showed that the deletion on derivative chromosome 1 is between 4.2 and 6.1 Mb, and the deletion on derivative chromosome 7 is approximately 5.1 Mb, and that both are paternal in origin. The deletion on chromosome 7p encompasses the GLI3 gene that is causative for the Greig cephalopolysyndactyly, Pallister-Hall and some cases of Acrocallosal syndromes. We discuss the potential mechanisms of formation of the described CCR.
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PMID:Complex balanced translocation t(1;5;7)(p32.1;q14.3;p21.3) and two microdeletions del(1)(p31.1p31.1) and del(7)(p14.1p14.1) in a patient with features of Greig cephalopolysyndactyly and mental retardation. 1793 35

Defects in dendritic spines and synapses contribute to cognitive deficits in mental retardation syndromes and, potentially, Alzheimer disease. p21-activated kinases (PAKs) regulate actin filaments and morphogenesis of dendritic spines regulated by the Rho family GTPases Rac and Cdc42. We previously reported that active PAK was markedly reduced in Alzheimer disease cytosol, accompanied by downstream loss of the spine actin-regulatory protein Drebrin. beta-Amyloid (Abeta) oligomer was implicated in PAK defects. Here we demonstrate that PAK is aberrantly activated and translocated from cytosol to membrane in Alzheimer disease brain and in 22-month-old Tg2576 transgenic mice with Alzheimer disease. This active PAK coimmunoprecipitated with the small GTPase Rac and both translocated to granules. Abeta42 oligomer treatment of cultured hippocampal neurons induced similar effects, accompanied by reduction of dendrites that were protected by kinase-active but not kinase-dead PAK. Abeta42 oligomer treatment also significantly reduced N-methyl-d-aspartic acid receptor subunit NR2B phosphotyrosine labeling. The Src family tyrosine kinase inhibitor PP2 significantly blocked the PAK/Rac translocation but not the loss of p-NR2B in Abeta42 oligomer-treated neurons. Src family kinases are known to phosphorylate the Rac activator Tiam1, which has recently been shown to be Abeta-responsive. In addition, anti-oligomer curcumin comparatively suppressed PAK translocation in aged Tg2576 transgenic mice with Alzheimer amyloid pathology and in Abeta42 oligomer-treated cultured hippocampal neurons. Our results implicate aberrant PAK in Abeta oligomer-induced signaling and synaptic deficits in Alzheimer disease.
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PMID:p21-activated kinase-aberrant activation and translocation in Alzheimer disease pathogenesis. 1834 24


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