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排序方式: 共有1005条查询结果,搜索用时 125 毫秒
141.
TRPC6 is a glomerular slit diaphragm-associated channel required for normal renal function 总被引:27,自引:0,他引:27
Reiser J Polu KR Möller CC Kenlan P Altintas MM Wei C Faul C Herbert S Villegas I Avila-Casado C McGee M Sugimoto H Brown D Kalluri R Mundel P Smith PL Clapham DE Pollak MR 《Nature genetics》2005,37(7):739-744
Progressive kidney failure is a genetically and clinically heterogeneous group of disorders. Podocyte foot processes and the interposed glomerular slit diaphragm are essential components of the permeability barrier in the kidney. Mutations in genes encoding structural proteins of the podocyte lead to the development of proteinuria, resulting in progressive kidney failure and focal segmental glomerulosclerosis. Here, we show that the canonical transient receptor potential 6 (TRPC6) ion channel is expressed in podocytes and is a component of the glomerular slit diaphragm. We identified five families with autosomal dominant focal segmental glomerulosclerosis in which disease segregated with mutations in the gene TRPC6 on chromosome 11q. Two of the TRPC6 mutants had increased current amplitudes. These data show that TRPC6 channel activity at the slit diaphragm is essential for proper regulation of podocyte structure and function. 相似文献
142.
Monsuur AJ de Bakker PI Alizadeh BZ Zhernakova A Bevova MR Strengman E Franke L van't Slot R van Belzen MJ Lavrijsen IC Diosdado B Daly MJ Mulder CJ Mearin ML Meijer JW Meijer GA van Oort E Wapenaar MC Koeleman BP Wijmenga C 《Nature genetics》2005,37(12):1341-1344
Celiac disease is probably the best-understood immune-related disorder. The disease presents in the small intestine and results from the interplay between multiple genes and gluten, the triggering environmental factor. Although HLA class II genes explain 40% of the heritable risk, non-HLA genes accounting for most of the familial clustering have not yet been identified. Here we report significant and replicable association (P = 2.1 x 10(-6)) to a common variant located in intron 28 of the gene myosin IXB (MYO9B), which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. Individuals homozygous with respect to the at-risk allele have a 2.3-times higher risk of celiac disease (P = 1.55 x 10(-5)). This result is suggestive of a primary impairment of the intestinal barrier in the etiology of celiac disease, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier. 相似文献
143.
Jadeja S Smyth I Pitera JE Taylor MS van Haelst M Bentley E McGregor L Hopkins J Chalepakis G Philip N Perez Aytes A Watt FM Darling SM Jackson I Woolf AS Scambler PJ 《Nature genetics》2005,37(5):520-525
Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALXbeta-cadherin motif is important for normal functioning of FREM2. 相似文献
144.
Sickle cell anemia (SCA) is a paradigmatic single gene disorder caused by homozygosity with respect to a unique mutation at the beta-globin locus. SCA is phenotypically complex, with different clinical courses ranging from early childhood mortality to a virtually unrecognized condition. Overt stroke is a severe complication affecting 6-8% of individuals with SCA. Modifier genes might interact to determine the susceptibility to stroke, but such genes have not yet been identified. Using Bayesian networks, we analyzed 108 SNPs in 39 candidate genes in 1,398 individuals with SCA. We found that 31 SNPs in 12 genes interact with fetal hemoglobin to modulate the risk of stroke. This network of interactions includes three genes in the TGF-beta pathway and SELP, which is associated with stroke in the general population. We validated this model in a different population by predicting the occurrence of stroke in 114 individuals with 98.2% accuracy. 相似文献
145.
Clayton DG Walker NM Smyth DJ Pask R Cooper JD Maier LM Smink LJ Lam AC Ovington NR Stevens HE Nutland S Howson JM Faham M Moorhead M Jones HB Falkowski M Hardenbol P Willis TD Todd JA 《Nature genetics》2005,37(11):1243-1246
The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure. In genetics the first of these, in the form of population structure, has dominated recent debate. Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method by applying a variable downweighting to each SNP. 相似文献
146.
Atomic ordering in network glasses on length scales longer than nearest-neighbour length scales has long been a source of controversy. Detailed experimental information is therefore necessary to understand both the network properties and the fundamentals of glass formation. Here we address the problem by investigating topological and chemical ordering in structurally disordered AX2 systems by applying the method of isotopic substitution in neutron diffraction to glassy ZnCl2. This system may be regarded as a prototypical ionic network forming glass, provided that ion polarization effects are taken into account, and has thus been the focus of much attention. By experiment, we show that both the topological and chemical ordering are described by two length scales at distances greater than nearest-neighbour length scales. One of these is associated with the intermediate range, as manifested by the appearance in the measured diffraction patterns of a first sharp diffraction peak at 1.09(3) A(-1); the other is associated with an extended range, which shows ordering in the glass out to 62(4) A. We also find that these general features are characteristic of glassy GeSe2, a prototypical covalently bonded network material. The results therefore offer structural insight into those length scales that determine many important aspects of supercooled liquid and glass phenomenology. 相似文献
147.
Identifying the origin of primordial volatiles in the Earth's mantle provides a critical test between models that advocate magma-ocean equilibration with an early massive solar-nebula atmosphere and those that require subduction of volatiles implanted in late accreting material. Here we show that neon isotopes in the convecting mantle, resolved in magmatic CO2 well gases, are consistent with a volatile source related to solar corpuscular irradiation of accreting material. This contrasts with recent results that indicated a solar-nebula origin for neon in mantle plume material, which is thought to be sampling the deep mantle. Neon isotope heterogeneity in different mantle sources suggests that models in which the plume source supplies the convecting mantle with its volatile inventory require revision. Although higher than accepted noble gas concentrations in the convecting mantle may reduce the need for a deep mantle volatile flux, any such flux must be dominated by the neon (and helium) isotopic signature of late accreting material. 相似文献
148.
149.
How DNA repair proteins distinguish between the rare sites of damage and the vast expanse of normal DNA is poorly understood. Recognizing the mutagenic lesion 8-oxoguanine (oxoG) represents an especially formidable challenge, because this oxidized nucleobase differs by only two atoms from its normal counterpart, guanine (G). Here we report the use of a covalent trapping strategy to capture a human oxoG repair protein, 8-oxoguanine DNA glycosylase I (hOGG1), in the act of interrogating normal DNA. The X-ray structure of the trapped complex features a target G nucleobase extruded from the DNA helix but denied insertion into the lesion recognition pocket of the enzyme. Free energy difference calculations show that both attractive and repulsive interactions have an important role in the preferential binding of oxoG compared with G to the active site. The structure reveals a remarkably effective gate-keeping strategy for lesion discrimination and suggests a mechanism for oxoG insertion into the hOGG1 active site. 相似文献
150.
Hexameric ring-shaped ATPases of the AAA + (for ATPases associated with various cellular activities) superfamily power cellular processes in which macromolecular structures and complexes are dismantled or denatured, but the mechanisms used by these machine-like enzymes are poorly understood. By covalently linking active and inactive subunits of the ATPase ClpX to form hexamers, here we show that diverse geometric arrangements can support the enzymatic unfolding of protein substrates and translocation of the denatured polypeptide into the ClpP peptidase for degradation. These studies indicate that the ClpX power stroke is generated by ATP hydrolysis in a single subunit, rule out concerted and strict sequential ATP hydrolysis models, and provide evidence for a probabilistic sequence of nucleotide hydrolysis. This mechanism would allow any ClpX subunit in contact with a translocating polypeptide to hydrolyse ATP to drive substrate spooling into ClpP, and would prevent stalling if one subunit failed to bind or hydrolyse ATP. Energy-dependent machines with highly diverse quaternary architectures and molecular functions could operate by similar asymmetric mechanisms. 相似文献