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)

The promoter of the human fragile mental retardation gene (FMR1) was functionally analyzed in order to identify elements responsible for its regulation. Plasmids carrying the wild type or different deleted-promoter sequences driving the chloramphenicol acetyl transferase gene (CAT) were transiently transfected into the SK-N-SH cells and the CAT activity was assessed. Deletion studies suggested that major regulatory elements are present in a DNA region between positions -123 and -51. Gel mobility shift and footprinting assays using a DNA fragment encompassing that promoter region showed that SP1 and AP2 transcription factors could be involved in the functioning of the FMR1 promoter.
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PMID:Sp1 and AP2 transcription factors are required for the human fragile mental retardation promoter activity in SK-N-SH neuronal cells. 1061 27

The L1 adhesion molecule regulates axon growth and is mutated in the X-linked mental retardation syndrome CRASH (acronym for corpus callosum agenesis, retardation, aphasia, spastic paraplegia, hydrocephalus). A novel role for L1 as a potentiator of neuronal cell migration to extracellular matrix proteins through beta1 integrins and intracellular signaling to mitogen-activated protein (MAP) kinase was identified. L1 potentiated haptotactic migration of B35 neuroblastoma cells toward fibronectin, vitronectin, and laminin through the signaling intermediates c-Src, phosphatidylinositol-3 kinase, and MAP kinase. L1 potentiated migration toward fibronectin through alpha5beta1 integrin in human embryonic kidney 293 cells and depended on determinants of L1 endocytosis: dynamin I, c-Src, and the AP2/clathrin binding site (Arg-Ser-Leu-Glu) in the neuronal splice form of L1. L1 clustering on the cell surface enhanced the internalization of activated beta1 integrins and L1 into distinct endocytic vesicles. L1-potentiated migration, enhancement of beta1 integrin endocytosis, and activation of MAP kinase were coordinately inhibited by mutation of an RGD sequence in the sixth immunoglobulin-like domain of L1. Moreover, three CRASH mutations in the L1 cytoplasmic domain (1194L, S1224L, Y1229H), two of which interfere with ankyrin association, inhibited L1-potentiated migration and MAP kinase activation. Function-blocking antibodies to L1 and beta1 integrin retarded the migration of 5-bromo-2'-deoxyuridine-labeled mouse cerebellar granule cells in slice cultures, underscoring the potential physiological relevance of these findings. These studies suggest that L1 functionally interacts with beta1 integrins to potentiate neuronal migration toward extracellular matrix proteins through endocytosis and MAP kinase signaling, and that impairment of this function by L1 cytoplasmic domain mutations may contribute to neurological deficits in CRASH.
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PMID:The neural cell adhesion molecule L1 potentiates integrin-dependent cell migration to extracellular matrix proteins. 1207 89

Fragile X syndrome, the most common heritable form of mental retardation, is caused by silencing of the FMR1 (fragile X mental retardation-1 gene). The protein product of this gene, FMRP (fragile X mental retardation protein), is thought to be involved in the translational regulation of mRNAs important for learning and memory. In mammals, there are two homologues of FMRP, namely FXR1P (fragile X-related protein 1) and FXR2P. Disruption of Fxr2 in mice produces learning and memory deficits, and Fmr1 and Fxr2 double-knockout mice have exaggerated impairments in certain neurobehavioral phenotypes relative to the single gene knockouts. This has led to the suggestion that FMR1 and FXR2 functionally overlap and that increasing the expression of FXR2P may ameliorate the symptoms of an FMRP deficiency. Interestingly, the region upstream of the FXR2 translation start site acts as a bidirectional promoter in rodents, driving transcription of an alternative transcript encoding the ABP (androgen-binding protein) [aABP (alternative ABP promoter)]. To understand the regulation of the human FXR2 gene, we cloned the evolutionarily conserved region upstream of the FXR2 translation start site and showed that it also has bidirectional promoter activity in both neuronal and muscle cells as evidenced by luciferase reporter assay studies. Alignment of the human, mouse, rat, rabbit and dog promoters reveals several highly conserved transcription factor-binding sites. Gel electrophoretic mobility-shift assays, chromatin immunoprecipitation studies and co-transfection experiments with plasmids expressing these transcription factors or dominant-negative versions of these factors showed that NF-YA (nuclear transcription factor Yalpha), AP2 (activator protein 2), Nrf1 (nuclear respiratory factor/alpha-Pal) and Sp1 (specificity protein 1) all bind to the FXR2 promoter both in vitro and in vivo and positively regulate the FXR2 promoter.
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PMID:NF-Y, AP2, Nrf1 and Sp1 regulate the fragile X-related gene 2 (FXR2). 1688 7

The Lowe syndrome (LS) is a life-threatening, developmental disease characterized by mental retardation, cataracts and renal failure. Although this human illness has been linked to defective function of the phosphatidylinositol 5-phosphatase, Ocrl1 (Oculo-Cerebro-Renal syndrome of Lowe protein 1), the mechanism by which this enzyme deficiency triggers the disease is not clear. Ocrl1 is known to localize mainly to the Golgi apparatus and endosomes, however it translocates to plasma membrane ruffles upon cell stimulation with growth factors. The functional implications of this inducible translocation to the plasma membrane are presently unknown. Here we show that Ocrl1 is required for proper cell migration, spreading and fluid-phase uptake in both established cell lines and human dermal fibroblasts. We found that primary fibroblasts from two patients diagnosed with LS displayed defects in these cellular processes. Importantly, these abnormalities were suppressed by expressing wild-type Ocrl1 but not by a phosphatase-deficient mutant. Interestingly, the homologous human PI-5-phosphatase, Inpp5b, was unable to complement the Ocrl1-dependent cell migration defect. Further, Ocrl1 variants that cannot bind the endocytic adaptor AP2 or clathrin, like Inpp5b, were less apt to rescue the migration phenotype. However, no defect in membrane recruitment of AP2/clathrin or in transferrin endocytosis by patient cells was detected. Collectively, our results suggest that Ocrl1, but not Inpp5b, is involved in ruffle-mediated membrane remodeling. Our results provide new elements for understanding how Ocrl1 deficiency leads to the abnormalities associated with the LS.
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PMID:Lowe syndrome patient fibroblasts display Ocrl1-specific cell migration defects that cannot be rescued by the homologous Inpp5b phosphatase. 1970 Apr 99