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1.
Rui M Costa Nikolai B Federov Jeff H Kogan Geoffrey G Murphy Joel Stern Masuo Ohno Raju Kucherlapati Tyler Jacks Alcino J Silva 《Nature》2002,415(6871):526-530
Neurofibromatosis type I (NF1) is one of the most common single-gene disorders that causes learning deficits in humans. Mice carrying a heterozygous null mutation of the Nfl gene (Nfl(+/-) show important features of the learning deficits associated with NF1 (ref. 2). Although neurofibromin has several known properties and functions, including Ras GTPase-activating protein activity, adenylyl cyclase modulation and microtubule binding, it is unclear which of these are essential for learning in mice and humans. Here we show that the learning deficits of Nf1(+/-) mice can be rescued by genetic and pharmacological manipulations that decrease Ras function. We also show that the Nf1(+/-) mice have increased GABA (gamma-amino butyric acid)-mediated inhibition and specific deficits in long-term potentiation, both of which can be reversed by decreasing Ras function. Our results indicate that the learning deficits associated with NF1 may be caused by excessive Ras activity, which leads to impairments in long-term potentiation caused by increased GABA-mediated inhibition. Our findings have implications for the development of treatments for learning deficits associated with NF1. 相似文献
2.
Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease 总被引:16,自引:0,他引:16
Sakuntabhai A Ruiz-Perez V Carter S Jacobsen N Burge S Monk S Smith M Munro CS O'Donovan M Craddock N Kucherlapati R Rees JL Owen M Lathrop GM Monaco AP Strachan T Hovnanian A 《Nature genetics》1999,21(3):271-277
Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2(+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca(2+)-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis. 相似文献
3.
Montgomery KT Lee E Miller A Lau S Shim C Decker J Chiu D Emerling S Sekhon M Kim R Lenz J Han J Ioshikhes I Renault B Marondel I Yoon SJ Song K Murty VV Scherer S Yonescu R Kirsch IR Ried T McPherson J Gibbs R Kucherlapati R 《Nature》2001,409(6822):945-946
Our sequence-tagged site-content map of chromosome 12 is now integrated with the whole-genome fingerprinting effort. It provides accurate and nearly complete bacterial clone coverage of chromosome 12. We propose that this integrated mapping protocol serves as a model for constructing physical maps for entire genomes. 相似文献
4.
Cancer. Telomerase meets its mismatch 总被引:6,自引:0,他引:6
5.
Pellegata NS Dieguez-Lucena JL Joensuu T Lau S Montgomery KT Krahe R Kivelä T Kucherlapati R Forsius H de la Chapelle A 《Nature genetics》2000,25(1):91-95
Specialized collagens and small leucine-rich proteoglycans (SLRPs) interact to produce the transparent corneal structure. In cornea plana, the forward convex curvature is flattened, leading to a decrease in refraction. A more severe, recessively inherited form (CNA2; MIM 217300) and a milder, dominantly inherited form (CNA1; MIM 121400) exist. CNA2 is a rare disorder with a worldwide distribution, but a high prevalence in the Finnish population. The gene mutated in CNA2 was assigned by linkage analysis to 12q (refs 4, 5), where there is a cluster of several SLRP genes. We cloned two additional SLRP genes highly expressed in cornea: KERA (encoding keratocan) in 12q and OGN (encoding osteoglycin) in 9q. Here we report mutations in KERA in 47 CNA2 patients: 46 Finnish patients are homozygous for a founder missense mutation, leading to the substitution of a highly conserved amino acid; and one American patient is homozygous for a mutation leading to a premature stop codon that truncates the KERA protein. Our data establish that mutations in KERA cause CNA2. CNA1 patients had no mutations in these proteoglycan genes. 相似文献
6.
Roberts AE Araki T Swanson KD Montgomery KT Schiripo TA Joshi VA Li L Yassin Y Tamburino AM Neel BG Kucherlapati RS 《Nature genetics》2007,39(1):70-74
Noonan syndrome, the most common single-gene cause of congenital heart disease, is characterized by short stature, characteristic facies, learning problems and leukemia predisposition. Gain-of-function mutations in PTPN11, encoding the tyrosine phosphatase SHP2, cause approximately 50% of Noonan syndrome cases. SHP2 is required for RAS-ERK MAP kinase (MAPK) cascade activation, and Noonan syndrome mutants enhance ERK activation ex vivo and in mice. KRAS mutations account for <5% of cases of Noonan syndrome, but the gene(s) responsible for the remainder are unknown. We identified missense mutations in SOS1, which encodes an essential RAS guanine nucleotide-exchange factor (RAS-GEF), in approximately 20% of cases of Noonan syndrome without PTPN11 mutation. The prevalence of specific cardiac defects differs in SOS1 mutation-associated Noonan syndrome. Noonan syndrome-associated SOS1 mutations are hypermorphs encoding products that enhance RAS and ERK activation. Our results identify SOS1 mutants as a major cause of Noonan syndrome, representing the first example of activating GEF mutations associated with human disease and providing new insights into RAS-GEF regulation. 相似文献
7.
S. Mastanaiah D. Chengal Raju K. S. Swami 《Cellular and molecular life sciences : CMLS》1977,33(8):1051-1052
Summary The activity of isocitrate dehydrogenase was assayed in the pedipalpal muscle and hepatopancreas of scorption, Heterometrus fulvipes. The enzyme activity showed a circadian rhythmicity with a peak value at 20.00 h in both the tissues. 相似文献
8.
R. V. Krishnamoorthy D. Chengal Raju V. Chandrasekharam 《Cellular and molecular life sciences : CMLS》1971,27(12):1408-1409
Zusammenfassung Es wird gezeigt, dass die erhöhte autolytische Abbaugeschwindigkeit im denervierten Muskel von Bedeutung für den Proteinumsatz ist und immer noch das zentrale Problem der Veränderungen darstellt, die bei Denervierung — hier Durchschneidung des Ischiadicus — auftreten. 相似文献
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10.
Danda Srinivas Rao Tadiparthi Venkata VijayaKumar Sripada Subba Rao Swarna Prabhakar Guntamadugu Bhaskar Raju 《矿物冶金与材料学报》2011,18(5):515-522
The recovery of iron from the screw classifier overflow slimes by direct flotation was studied. The relative effectiveness of sodium silicates with different silica-to-soda mole ratios as depressants for silica and silicate bearing minerals was investigated. Silica-to-soda mole ratio and silicate dosage were found to have significant effect on the separation efficiency. The results show that an increase of Fe content in the concentrate is observed with concomitant reduction in SiO2 and Al2O3 levels when a particular type of sodium silicate at a proper dosage is used. The concentrate of 58.89wt% Fe, 4.68wt% SiO2, and 5.28wt% Al2O3 with the weight recovery of 38.74% and the metal recovery of 41.13% can be obtained from the iron ore slimes with 54.44wt% Fe, 6.72wt% SiO2, and 6.80wt% Al2O3, when Na2SiO3 with a silica-to-soda mole ratio of 2.19 is used as a depressant at a feed rate of 0.2 kg/t. 相似文献