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Infantile-onset symptomatic epilepsy syndrome caused by a homozygous loss-of-function mutation of GM3 synthase 总被引:8,自引:0,他引:8
Simpson MA Cross H Proukakis C Priestman DA Neville DC Reinkensmeier G Wang H Wiznitzer M Gurtz K Verganelaki A Pryde A Patton MA Dwek RA Butters TD Platt FM Crosby AH 《Nature genetics》2004,36(11):1225-1229
We identified an autosomal recessive infantile-onset symptomatic epilepsy syndrome associated with developmental stagnation and blindness. Assuming a founder effect in a large Old Order Amish pedigree, we carried out a genome-wide screen for linkage and identified a single region of homozygosity on chromosome 2p12-p11.2 spanning 5.1 cM (maximum lod score of 6.84). We sequenced genes in the region and identified a nonsense mutation in SIAT9, which is predicted to result in the premature termination of the GM3 synthase enzyme (also called lactosylceramide alpha-2,3 sialyltransferase). GM3 synthase is a member of the sialyltransferase family and catalyzes the initial step in the biosynthesis of most complex gangliosides from lactosylceramide. Biochemical analysis of plasma glycosphingolipids confirmed that affected individuals lack GM3 synthase activity, as marked by a complete lack of GM3 ganglioside and its biosynthetic derivatives and an increase in lactosylceramide and its alternative derivatives. Although the relationship between defects in ganglioside catabolism and a range of lysosomal storage diseases is well documented, this is the first report, to our knowledge, of a disruption of ganglioside biosynthesis associated with human disease. 相似文献
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Ross MT Grafham DV Coffey AJ Scherer S McLay K Muzny D Platzer M Howell GR Burrows C Bird CP Frankish A Lovell FL Howe KL Ashurst JL Fulton RS Sudbrak R Wen G Jones MC Hurles ME Andrews TD Scott CE Searle S Ramser J Whittaker A Deadman R Carter NP Hunt SE Chen R Cree A Gunaratne P Havlak P Hodgson A Metzker ML Richards S Scott G Steffen D Sodergren E Wheeler DA Worley KC Ainscough R Ambrose KD Ansari-Lari MA Aradhya S Ashwell RI Babbage AK Bagguley CL Ballabio A Banerjee R Barker GE Barlow KF 《Nature》2005,434(7031):325-337
The human X chromosome has a unique biology that was shaped by its evolution as the sex chromosome shared by males and females. We have determined 99.3% of the euchromatic sequence of the X chromosome. Our analysis illustrates the autosomal origin of the mammalian sex chromosomes, the stepwise process that led to the progressive loss of recombination between X and Y, and the extent of subsequent degradation of the Y chromosome. LINE1 repeat elements cover one-third of the X chromosome, with a distribution that is consistent with their proposed role as way stations in the process of X-chromosome inactivation. We found 1,098 genes in the sequence, of which 99 encode proteins expressed in testis and in various tumour types. A disproportionately high number of mendelian diseases are documented for the X chromosome. Of this number, 168 have been explained by mutations in 113 X-linked genes, which in many cases were characterized with the aid of the DNA sequence. 相似文献
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Pei H Zhang L Luo K Qin Y Chesi M Fei F Bergsagel PL Wang L You Z Lou Z 《Nature》2011,470(7332):124-128
p53-binding protein 1 (53BP1) is known to be an important mediator of the DNA damage response, with dimethylation of histone H4 lysine 20 (H4K20me2) critical to the recruitment of 53BP1 to double-strand breaks (DSBs). However, it is not clear how 53BP1 is specifically targeted to the sites of DNA damage, as the overall level of H4K20me2 does not seem to increase following DNA damage. It has been proposed that DNA breaks may cause exposure of methylated H4K20 previously buried within the chromosome; however, experimental evidence for such a model is lacking. Here we found that H4K20 methylation actually increases locally upon the induction of DSBs and that methylation of H4K20 at DSBs is mediated by the histone methyltransferase MMSET (also known as NSD2 or WHSC1) in mammals. Downregulation of MMSET significantly decreases H4K20 methylation at DSBs and the subsequent accumulation of 53BP1. Furthermore, we found that the recruitment of MMSET to DSBs requires the γH2AX-MDC1 pathway; specifically, the interaction between the MDC1 BRCT domain and phosphorylated Ser?102 of MMSET. Thus, we propose that a pathway involving γH2AX-MDC1-MMSET regulates the induction of H4K20 methylation on histones around DSBs, which, in turn, facilitates 53BP1 recruitment. 相似文献
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This paper describes four case studies of the practice of vision development in four utilities organisations. Important observations emerge about current practice; for example, tensions can be observed in organisations struggling to satisfy the expectations of a diverse range of stakeholders. Formal methodologies for visioning are rarely adopted in vision development; rather more informal processes of debate are preferred. Difficulties with internal communication and staff buy-in to the vision are also identified. Comparisons are drawn with the results of previous work on visioning in the financial services sector. 相似文献
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New cell lines from mouse epiblast share defining features with human embryonic stem cells 总被引:3,自引:0,他引:3
Tesar PJ Chenoweth JG Brook FA Davies TJ Evans EP Mack DL Gardner RL McKay RD 《Nature》2007,448(7150):196-199
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Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus 总被引:19,自引:0,他引:19
Cheng MY Bullock CM Li C Lee AG Bermak JC Belluzzi J Weaver DR Leslie FM Zhou QY 《Nature》2002,417(6887):405-410
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B. Tabakoff Frances Moses S. R. Philips A. A. Boulton 《Cellular and molecular life sciences : CMLS》1977,33(3):380-381
Summary Tranylcypromine produces behavioral excitation while pargyline produces depression. Tranylcypromine increased brain tryptophan which led to an accumulation of tryptamine. The levels of tryptamine after tranylcypromine were found to be 3 times those found after pargyline.This work was supported in part by U. S. Public Health Service Grants NS-12759 and AA-2696, State of Illinois Department of Mental Health, the Psychiatric Services Branch, Province of Saskatchewan, and the Medical Research Council of Canada, who have provided continuing financial support.Acknowledgments. We thank Dr B. A. Davis for synthesizing the deuterated internal standards, Dr D. A. Durden for supervising the mass spectrometric analyses, and Mr H. Miyashita, Mr N. F. Binder and Miss E. E. Johnson for skilled technical assistance. 相似文献