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Zankl A Neumann L Ignatius J Nikkels P Schrander-Stumpel C Mortier G Omran H Wright M Hilbert K Bonafé L Spranger J Zabel B Superti-Furga A 《American journal of medical genetics. Part A》2005,(1):61-67
Platyspondylic lethal skeletal dysplasia (PLSD) Torrance type (PLSD-T) is a rare skeletal dysplasia characterized by platyspondyly, brachydactyly, and metaphyseal changes. Generally a perinatally lethal disease, a few long-term survivors have been reported. Recently, mutations in the carboxy-propeptide of type II collagen have been identified in two patients with PLSD-T, indicating that PLSD-T is a type 2 collagen-associated disorder. We studied eight additional cases of PLSD-T and found that all had mutations in the C-propeptide domain of COL2A1. The mutational spectrum includes missense, stop codon and frameshift mutations. All non-sense mutations were located in the last exon, where they would escape non-sense-mediated RNA-decay. We conclude that PLSD-T is caused by mutations in the C-propeptide domain of COL2A1, which lead to biosynthesis of an altered collagen chain (as opposed to a null allele). Similar mutations have recently been found to be the cause of spondyloperipheral dysplasia, a non-lethal dominant disorder whose clinical and radiographical features overlap those of the rare long-term survivors with PLSD-T. Thus, spondyloperipheral dysplasia and PLSD-T constitute a novel subfamily within the type II collagenopathies, associated with specific mutations in the C-propeptide domain and characterized by distinctive radiological features including metaphyseal changes and brachydactyly that set them apart from other type 2 collagenopathies associated with mutations in the triple-helical domain of COL2A1. The specific phenotype of C-propeptide mutations could result from a combination of diminished collagen fibril formation, toxic effects through the accumulation of unfolded collagen chains inside the chondrocytes, and alteration of a putative signaling function of the carboxy-propeptide of type 2 collagen. 相似文献
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Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by a functional haploinsufficiency of genes encoding for ribosomal proteins. Recently, a case study reported a patient who became transfusion-independent in response to treatment with the amino acid L-leucine. Therefore, we have validated the therapeutic effect of L-leucine using our recently generated mouse model for RPS19-deficient DBA. Administration of L-leucine significantly improved the anemia in Rps19-deficient mice (19% improvement in hemoglobin concentration; 18% increase in the number of erythrocytes), increased the bone marrow cellularity, and alleviated stress hematopoiesis. Furthermore, the therapeutic response to L-leucine appeared specific for Rps19-deficient hematopoiesis and was associated with down-regulation of p53 activity. Our study supports the rationale for clinical trials of L-leucine as a therapeutic agent for DBA. 相似文献
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Pekka Jaako Shubhranshu Debnath Karin Olsson Ute Modlich Michael Rothe Axel Schambach Johan Flygare Stefan Karlsson 《Haematologica》2014,99(12):1792-1798
Diamond-Blackfan anemia is a congenital erythroid hypoplasia caused by functional haploinsufficiency of genes encoding ribosomal proteins. Mutations involving the ribosomal protein S19 gene are detected in 25% of patients. Enforced expression of ribosomal protein S19 improves the overall proliferative capacity, erythroid colony-forming potential and erythroid differentiation of hematopoietic progenitors from ribosomal protein S19-deficient patients in vitro and in vivo following xenotransplantation. However, studies using animal models are needed to assess the therapeutic efficacy and safety of the viral vectors. In the present study we have validated the therapeutic potential of gene therapy using mouse models of ribosomal protein S19-deficient Diamond-Blackfan anemia. Using lentiviral gene transfer we demonstrated that enforced expression of ribosomal protein S19 cures the anemia and lethal bone marrow failure in recipients transplanted with ribosomal protein S19-deficient cells. Furthermore, gene-corrected ribosomal protein S19-deficient cells showed an increased pan-hematopoietic contribution over time compared to untransduced cells without signs of vector-mediated toxicity. Our study provides a proof of principle for the development of clinical gene therapy to cure ribosomal protein 19-deficient Diamond-Blackfan anemia. 相似文献
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Release of platelet 5-hydroxytryptamine by some anorexic and other sympathomimetics and their acetyl derivatives 总被引:1,自引:0,他引:1
The effect on 5-hydroxytryptamine release from rabbit platelets to plasma of ten known sympathomimetic or anorectic phenethylamines and eight N- or O-acetyl derivatives of these substances were studied in order to find possible structure-action relationships and a possible correlation to the pulmonary hypertension inducing ability of some anorexigens. Among the mainly indirectly acting sympathomimetics amphetamine and ephedrine showed a similar high 5HT-releasing effect. Tyramine was slightly weaker, while the direct acting phenylephrine (metaoxedrine) and orciprenaline were much weaker. Acetylation increased the 5HT releasing effect of amphetamine, ephedrine and tyramine but decreased this effect of phenylephrine and orciprenaline. Among the anorectic phenethylamines the 5HT-releasing effect decreased in the following order, aminorex, amphetamine, clophorex, chlorphentermine, diethylpropion (amphepramon), phentermine. With regard to aminorex, which is a releaser of platelet 5HT and an inhibitor of both MAO activity and 5HT uptake in pulmonary tissue, it seems possible that the pulmonary hypertension can be caused by high concentration of free 5HT. 相似文献
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Glucocorticoids improve erythroid progenitor maintenance and dampen Trp53 response in a mouse model of Diamond–Blackfan anaemia
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Sara E. Sjögren Kavitha Siva Shamit Soneji Amee J. George Marcus Winkler Pekka Jaako Marcin Wlodarski Stefan Karlsson Ross D. Hannan Johan Flygare 《British journal of haematology》2015,171(4):517-529
Diamond–Blackfan anaemia (DBA) is a rare congenital disease causing severe anaemia and progressive bone marrow failure. The majority of patients carry mutations in ribosomal proteins, which leads to depletion of erythroid progenitors in the bone marrow. As many as 40% of all DBA patients receive glucocorticoids to alleviate their anaemia. However, despite their use in DBA treatment for more than half a century, the therapeutic mechanisms of glucocorticoids remain largely unknown. Therefore we sought to study disease specific effects of glucocorticoid treatment using a ribosomal protein s19 (Rps19) deficient mouse model of DBA. This study determines for the first time that a mouse model of DBA can respond to glucocorticoid treatment, similar to DBA patients. Our results demonstrate that glucocorticoid treatment reduces apoptosis, rescues erythroid progenitor depletion and premature differentiation of erythroid cells. Furthermore, glucocorticoids prevent Trp53 activation in Rps19‐deficient cells‐ in a disease‐specific manner. Dissecting the therapeutic mechanisms behind glucocorticoid treatment of DBA provides indispensible insight into DBA pathogenesis. Identifying mechanisms important for DBA treatment also enables development of more disease‐specific treatments of DBA. 相似文献
7.
Martti Marvola Sinikka Fristrm Erik Klinge Jaakko Halmekoski 《Basic & clinical pharmacology & toxicology》1976,39(3):344-352
Abstract The bull retractor penis muscle was used to compare the α–adrenergic effect of adrenaline, noradrenaline, methoxamine, phenylephrine, metaraminol, tyramine, amphetamine, ephedrine and orciprenaline with that of some of their O– and N–acetyl derivatives. The effect of cocaine on the responses to the drugs was also examined. Methoxamine exhibited the strongest stimulant potency on this smooth muscle. The ED50 of the other parent compounds decreased in the following order: adrenaline, noradrenaline, phenylephrine, ephedrine, metaraminol, amphetamine, tyramine. N–acetylation decreased very clearly or even abolished the effect of the drugs. O–acetylation also decreased the effect but not as much as N–acetylation. The effects of the O–acetyl derivatives were probably at least partly due to the corresponding parent compounds released after deacetylation. The very weak effects of the N–acetyl derivatives suggest that little if any N–deacetylation occurred during the experiments. 相似文献
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Follow-up report on the diagnosis of diabetes mellitus 总被引:138,自引:0,他引:138
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Francesco Sambo Alberto Malovini Niina Sandholm Monica Stavarachi Carol Forsblom Ville-Petteri Mäkinen Valma Harjutsalo Raija Lithovius Daniel Gordin Maija Parkkonen Markku Saraheimo Lena M. Thorn Nina Tolonen Johan Wadén Bing He Anne-May Österholm Jaako Tuomilehto Maria Lajer Rany M. Salem Amy Jayne McKnight Lise Tarnow Nicolae M. Panduru Nicola Barbarini Barbara Di Camillo Gianna M. Toffolo Karl Tryggvason Riccardo Bellazzi Claudio Cobelli Per-Henrik Groop 《Diabetologia》2014,57(8):1611-1622