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PTC124 targets genetic disorders caused by nonsense mutations 总被引:1,自引:0,他引:1
Welch EM Barton ER Zhuo J Tomizawa Y Friesen WJ Trifillis P Paushkin S Patel M Trotta CR Hwang S Wilde RG Karp G Takasugi J Chen G Jones S Ren H Moon YC Corson D Turpoff AA Campbell JA Conn MM Khan A Almstead NG Hedrick J Mollin A Risher N Weetall M Yeh S Branstrom AA Colacino JM Babiak J Ju WD Hirawat S Northcutt VJ Miller LL Spatrick P He F Kawana M Feng H Jacobson A Peltz SW Sweeney HL 《Nature》2007,447(7140):87-91
Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options. 相似文献
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Spontaneous excision of a large composite transposable element of Drosophila melanogaster 总被引:1,自引:0,他引:1
The TE1 family of transposable elements (TEs) of Drosophila consists of unusually large transposons, cytologically visible in larval polytene chromosomes as one or more bands. They are composite elements, as their termini consist of foldback (FB) sequences which are themselves transposable. The location of FB elements at the termini of transposable elements suggests that these sequences have a direct role in the genetic instability of TEs. To investigate the structural and phenotypic consequence of TE excision, we have cloned genomic DNA required for the expression of the no-ocelli (noc) gene of Drosophila; this gene has been mutated by the insertion of TE146, a member of the TE1 family carrying six polytene chromosome bands including functional copies of the white (w+) and roughest (rst+) genes. As reported here, our experiments indicate that the spontaneous excision of TE146, which results in the loss of the w+ and rst+ markers, can occur either as a single-step event or following a partial internal deletion. In either case, the end product is an imprecise excision in which a residual portion of the element, varying in size from 3 to 10 kilobases (kb), is left at the insertion site. These residual sequences share homology with the FB family. Furthermore, despite their imprecise nature, all these spontaneous excisions restore a wild-type noc+ phenotype. 相似文献
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Seventeen subadult, hatchery-reared razorback suckers ( Xyrauchen texanus ; (  ̄x = 456 mm total length) were implanted with sonic transmitters and tracked for 23 months in the lower 89.6 km of the San Juan River (San Juan arm of Lake Powell, Utah). Fish were released at 2 sites, and 9 made extensive up- and downstream movements (  ̄x = 47.8 km; contact was lost with 4, and 4 others presumably died or lost their transmitters). The San Juan arm is primarily inundated canyon; however, most fish contacts occurred in shallow coves and shoreline with thick stands of flooded salt cedar in the upper inflow area. Eight fish frequented the Piute Farms river/lake mixing zone, and at least 4 moved upstream into the San Juan River. Seven fish were found in 2 aggregations in spring (3 fish in Neskahi Bay in 1996 and 4 fish just downstream of Piute Farms in 1997), and these may have been associated with spawning activity. Continued presence of razorback suckers in the Piute Farms area and lower San Juan River suggests the San Juan inflow to Lake Powell could be used as an alternate stocking site for reintroduction efforts. 相似文献
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AA Pezzulo XX Tang MJ Hoegger MH Alaiwa S Ramachandran TO Moninger PH Karp CL Wohlford-Lenane HP Haagsman M van Eijk B Bánfi AR Horswill DA Stoltz PB McCray MJ Welsh J Zabner 《Nature》2012,487(7405):109-113
Cystic fibrosis (CF) is a life-shortening disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Although bacterial lung infection and the resulting inflammation cause most of the morbidity and mortality, how the loss of CFTR function first disrupts airway host defence has remained uncertain. To investigate the abnormalities that impair elimination when a bacterium lands on the pristine surface of a newborn CF airway, we interrogated the viability of individual bacteria immobilized on solid grids and placed onto the airway surface. As a model, we studied CF pigs, which spontaneously develop hallmark features of CF lung disease. At birth, their lungs lack infection and inflammation, but have a reduced ability to eradicate bacteria. Here we show that in newborn wild-type pigs, the thin layer of airway surface liquid (ASL) rapidly kills bacteria in vivo, when removed from the lung and in primary epithelial cultures. Lack of CFTR reduces bacterial killing. We found that the ASL pH was more acidic in CF pigs, and reducing pH inhibited the antimicrobial activity of ASL. Reducing ASL pH diminished bacterial killing in wild-type pigs, and, conversely, increasing ASL pH rescued killing in CF pigs. These results directly link the initial host defence defect to the loss of CFTR, an anion channel that facilitates HCO(3)(-) transport. Without CFTR, airway epithelial HCO(3)(-) secretion is defective, the ASL pH falls and inhibits antimicrobial function, and thereby impairs the killing of bacteria that enter the newborn lung. These findings suggest that increasing ASL pH might prevent the initial infection in patients with CF, and that assaying bacterial killing could report on the benefit of therapeutic interventions. 相似文献
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Larsson P Oyston PC Chain P Chu MC Duffield M Fuxelius HH Garcia E Hälltorp G Johansson D Isherwood KE Karp PD Larsson E Liu Y Michell S Prior J Prior R Malfatti S Sjöstedt A Svensson K Thompson N Vergez L Wagg JK Wren BW Lindler LE Andersson SG Forsman M Titball RW 《Nature genetics》2005,37(2):153-159
Francisella tularensis is one of the most infectious human pathogens known. In the past, both the former Soviet Union and the US had programs to develop weapons containing the bacterium. We report the complete genome sequence of a highly virulent isolate of F. tularensis (1,892,819 bp). The sequence uncovers previously uncharacterized genes encoding type IV pili, a surface polysaccharide and iron-acquisition systems. Several virulence-associated genes were located in a putative pathogenicity island, which was duplicated in the genome. More than 10% of the putative coding sequences contained insertion-deletion or substitution mutations and seemed to be deteriorating. The genome is rich in IS elements, including IS630 Tc-1 mariner family transposons, which are not expected in a prokaryote. We used a computational method for predicting metabolic pathways and found an unexpectedly high proportion of disrupted pathways, explaining the fastidious nutritional requirements of the bacterium. The loss of biosynthetic pathways indicates that F. tularensis is an obligate host-dependent bacterium in its natural life cycle. Our results have implications for our understanding of how highly virulent human pathogens evolve and will expedite strategies to combat them. 相似文献
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We evaluated distribution, habitat use, spawning, and species associations of the endangered humpback chub ( Gila cypha ) in the Yampa and Green rivers, Dinosaur National Monument, from 1986 to 1989. Adult and juvenile humpback chub were captured in high-gradient reaches of Yampa and Whirlpool canyons where they were rare ( n = 133, G. robusta ) were widely distributed in eddies, pools, runs, and riffles. Humpback chub ( n = 39) and roundtail chub ( n = 242) in reproductive condition were sympatric in eddy habitats during the 5-6 week period following highest spring runoff. River temperatures at this time averaged about 20 C. Nonnative channel catfish ( Ictalurus punctatus ) were abundant in eddies yielding humpback and roundtail chubs, suggesting a potential for negative interactions between the native and introduced fishes. 相似文献
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The alpha 1 domain of the HLA-DR molecule is essential for high-affinity binding of the toxic shock syndrome toxin-1 总被引:7,自引:0,他引:7
Several exoproteins from the bacterium Staphylococcus aureus are highly potent polyclonal activators of T cells in the presence of cells bearing class II antigens of the major histocompatibility complex (MHC). These toxins, including the toxic shock syndrome toxin (TSST-1), act at nanomolar concentrations, bind directly to class II molecules, and do not require the processing typical of nominal antigen. Each toxin is capable of stimulating a subpopulation of peripheral T lymphocytes bearing particular V beta sequences as part of their alpha beta T-cell receptors. It is not known how these so-called 'superantigens' bind to class II and how this binding stimulates T cells. In this study, the different affinities of TSST-1 for human class II molecules DR and DP were exploited to define the region of a class II molecule necessary for high-affinity binding. Using chimaeric alpha- and beta-chains of DR and DP expressed at the surface of transfected murine fibroblasts and a binding assay with TSST-1, it was shown that the alpha 1 domain of DR is essential for high-affinity binding, and further that TSST-1 binding did not prevent subsequent binding of a DR-restricted antigenic peptide. This is compatible with a model of superantigen making external contacts with both class II and T cell receptor, and suggests that the V beta portion of the T-cell receptor interacts with the nonpolymorphic alpha-chain of DR. 相似文献
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Wechsler J Greene M McDevitt MA Anastasi J Karp JE Le Beau MM Crispino JD 《Nature genetics》2002,32(1):148-152
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