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排序方式: 共有908条查询结果,搜索用时 397 毫秒
781.
782.
Rees MI Harvey K Pearce BR Chung SK Duguid IC Thomas P Beatty S Graham GE Armstrong L Shiang R Abbott KJ Zuberi SM Stephenson JB Owen MJ Tijssen MA van den Maagdenberg AM Smart TG Supplisson S Harvey RJ 《Nature genetics》2006,38(7):801-806
Hyperekplexia is a human neurological disorder characterized by an excessive startle response and is typically caused by missense and nonsense mutations in the gene encoding the inhibitory glycine receptor (GlyR) alpha1 subunit (GLRA1). Genetic heterogeneity has been confirmed in rare sporadic cases, with mutations affecting other postsynaptic glycinergic proteins including the GlyR beta subunit (GLRB), gephyrin (GPHN) and RhoGEF collybistin (ARHGEF9). However, many individuals diagnosed with sporadic hyperekplexia do not carry mutations in these genes. Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia. Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes. SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites. 相似文献
783.
Beales PL Bland E Tobin JL Bacchelli C Tuysuz B Hill J Rix S Pearson CG Kai M Hartley J Johnson C Irving M Elcioglu N Winey M Tada M Scambler PJ 《Nature genetics》2007,39(6):727-729
Jeune asphyxiating thoracic dystrophy, an autosomal recessive chondrodysplasia, often leads to death in infancy because of a severely constricted thoracic cage and respiratory insufficiency; retinal degeneration, cystic renal disease and polydactyly may be complicating features. We show that IFT80 mutations underlie a subset of Jeune asphyxiating thoracic dystrophy cases, establishing the first association of a defective intraflagellar transport (IFT) protein with human disease. Knockdown of ift80 in zebrafish resulted in cystic kidneys, and knockdown in Tetrahymena thermophila produced shortened or absent cilia. 相似文献
784.
The heterochronic maize mutant Corngrass1 results from overexpression of a tandem microRNA 总被引:5,自引:0,他引:5
Retention of juvenile traits in the adult reproductive phase characterizes a process known as neoteny, and speculation exists over whether it has contributed to the evolution of new species. The dominant Corngrass1 (Cg1) mutant of maize is a neotenic mutation that results in phenotypes that may be present in the grass-like ancestors of maize. We cloned Cg1 and found that it encodes two tandem miR156 genes that are overexpressed in the meristem and lateral organs. Furthermore, a target of Cg1 is teosinte glume architecture1 (tga1), a gene known to have had a role in the domestication of maize from teosinte. Cg1 mutant plants overexpressing miR156 have lower levels of mir172, a microRNA that targets genes controlling juvenile development. By altering the relative levels of both microRNAs, it is possible to either prolong or shorten juvenile development in maize, thus providing a mechanism for how species-level heterochronic changes can occur in nature. 相似文献
785.
Population genomics of human gene expression 总被引:1,自引:0,他引:1
Stranger BE Nica AC Forrest MS Dimas A Bird CP Beazley C Ingle CE Dunning M Flicek P Koller D Montgomery S Tavaré S Deloukas P Dermitzakis ET 《Nature genetics》2007,39(10):1217-1224
Genetic variation influences gene expression, and this variation in gene expression can be efficiently mapped to specific genomic regions and variants. Here we have used gene expression profiling of Epstein-Barr virus-transformed lymphoblastoid cell lines of all 270 individuals genotyped in the HapMap Consortium to elucidate the detailed features of genetic variation underlying gene expression variation. We find that gene expression is heritable and that differentiation between populations is in agreement with earlier small-scale studies. A detailed association analysis of over 2.2 million common SNPs per population (5% frequency in HapMap) with gene expression identified at least 1,348 genes with association signals in cis and at least 180 in trans. Replication in at least one independent population was achieved for 37% of cis signals and 15% of trans signals, respectively. Our results strongly support an abundance of cis-regulatory variation in the human genome. Detection of trans effects is limited but suggests that regulatory variation may be the key primary effect contributing to phenotypic variation in humans. We also explore several methodologies that improve the current state of analysis of gene expression variation. 相似文献
786.
787.
Thomas RK Baker AC Debiasi RM Winckler W Laframboise T Lin WM Wang M Feng W Zander T MacConaill L Macconnaill LE Lee JC Nicoletti R Hatton C Goyette M Girard L Majmudar K Ziaugra L Wong KK Gabriel S Beroukhim R Peyton M Barretina J Dutt A Emery C Greulich H Shah K Sasaki H Gazdar A Minna J Armstrong SA Mellinghoff IK Hodi FS Dranoff G Mischel PS Cloughesy TF Nelson SF Liau LM Mertz K Rubin MA Moch H Loda M Catalona W Fletcher J Signoretti S Kaye F Anderson KC Demetri GD Dummer R Wagner S 《Nature genetics》2007,39(3):347-351
Systematic efforts are underway to decipher the genetic changes associated with tumor initiation and progression. However, widespread clinical application of this information is hampered by an inability to identify critical genetic events across the spectrum of human tumors with adequate sensitivity and scalability. Here, we have adapted high-throughput genotyping to query 238 known oncogene mutations across 1,000 human tumor samples. This approach established robust mutation distributions spanning 17 cancer types. Of 17 oncogenes analyzed, we found 14 to be mutated at least once, and 298 (30%) samples carried at least one mutation. Moreover, we identified previously unrecognized oncogene mutations in several tumor types and observed an unexpectedly high number of co-occurring mutations. These results offer a new dimension in tumor genetics, where mutations involving multiple cancer genes may be interrogated simultaneously and in 'real time' to guide cancer classification and rational therapeutic intervention. 相似文献
788.
Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes 总被引:7,自引:0,他引:7
Lowe CE Cooper JD Brusko T Walker NM Smyth DJ Bailey R Bourget K Plagnol V Field S Atkinson M Clayton DG Wicker LS Todd JA 《Nature genetics》2007,39(9):1074-1082
Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha (IL2RA) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5' regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70-2.45; P = 1.92 x 10(-28); control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA (P = 6.28 x 10(-28)), suggesting that an inherited lower immune responsiveness predisposes to T1D. 相似文献
789.
Richards A van den Maagdenberg AM Jen JC Kavanagh D Bertram P Spitzer D Liszewski MK Barilla-Labarca ML Terwindt GM Kasai Y McLellan M Grand MG Vanmolkot KR de Vries B Wan J Kane MJ Mamsa H Schäfer R Stam AH Haan J de Jong PT Storimans CW van Schooneveld MJ Oosterhuis JA Gschwendter A Dichgans M Kotschet KE Hodgkinson S Hardy TA Delatycki MB Hajj-Ali RA Kothari PH Nelson SF Frants RR Baloh RW Ferrari MD Atkinson JP 《Nature genetics》2007,39(9):1068-1070
Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias. 相似文献
790.
Sebaihia M Wren BW Mullany P Fairweather NF Minton N Stabler R Thomson NR Roberts AP Cerdeño-Tárraga AM Wang H Holden MT Wright A Churcher C Quail MA Baker S Bason N Brooks K Chillingworth T Cronin A Davis P Dowd L Fraser A Feltwell T Hance Z Holroyd S Jagels K Moule S Mungall K Price C Rabbinowitsch E Sharp S Simmonds M Stevens K Unwin L Whithead S Dupuy B Dougan G Barrell B Parkhill J 《Nature genetics》2006,38(7):779-786
We determined the complete genome sequence of Clostridium difficile strain 630, a virulent and multidrug-resistant strain. Our analysis indicates that a large proportion (11%) of the genome consists of mobile genetic elements, mainly in the form of conjugative transposons. These mobile elements are putatively responsible for the acquisition by C. difficile of an extensive array of genes involved in antimicrobial resistance, virulence, host interaction and the production of surface structures. The metabolic capabilities encoded in the genome show multiple adaptations for survival and growth within the gut environment. The extreme genome variability was confirmed by whole-genome microarray analysis; it may reflect the organism's niche in the gut and should provide information on the evolution of virulence in this organism. 相似文献