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121.
Rost S Fregin A Ivaskevicius V Conzelmann E Hörtnagel K Pelz HJ Lappegard K Seifried E Scharrer I Tuddenham EG Müller CR Strom TM Oldenburg J 《Nature》2004,427(6974):537-541
Coumarin derivatives such as warfarin represent the therapy of choice for the long-term treatment and prevention of thromboembolic events. Coumarins target blood coagulation by inhibiting the vitamin K epoxide reductase multiprotein complex (VKOR). This complex recycles vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor that is essential for the post-translational gamma-carboxylation of several blood coagulation factors. Despite extensive efforts, the components of the VKOR complex have not been identified. The complex has been proposed to be involved in two heritable human diseases: combined deficiency of vitamin-K-dependent clotting factors type 2 (VKCFD2; Online Mendelian Inheritance in Man (OMIM) 607473), and resistance to coumarin-type anticoagulant drugs (warfarin resistance, WR; OMIM 122700). Here we identify, by using linkage information from three species, the gene vitamin K epoxide reductase complex subunit 1 (VKORC1), which encodes a small transmembrane protein of the endoplasmic reticulum. VKORC1 contains missense mutations in both human disorders and in a warfarin-resistant rat strain. Overexpression of wild-type VKORC1, but not VKORC1 carrying the VKCFD2 mutation, leads to a marked increase in VKOR activity, which is sensitive to warfarin inhibition. 相似文献
122.
Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies 总被引:24,自引:0,他引:24
Haug K Warnstedt M Alekov AK Sander T Ramírez A Poser B Maljevic S Hebeisen S Kubisch C Rebstock J Horvath S Hallmann K Dullinger JS Rau B Haverkamp F Beyenburg S Schulz H Janz D Giese B Müller-Newen G Propping P Elger CE Fahlke C Lerche H Heils A 《Nature genetics》2003,33(4):527-532
Idiopathic generalized epilepsy (IGE) is an inherited neurological disorder affecting about 0.4% of the world's population. Mutations in ten genes causing distinct forms of idiopathic epilepsy have been identified so far, but the genetic basis of many IGE subtypes is still unknown. Here we report a gene associated with the four most common IGE subtypes: childhood and juvenile absence epilepsy (CAE and JAE), juvenile myoclonic epilepsy (JME), and epilepsy with grand mal seizures on awakening (EGMA; ref. 8). We identified three different heterozygous mutations in the chloride-channel gene CLCN2 in three unrelated families with IGE. These mutations result in (i) a premature stop codon (M200fsX231), (ii) an atypical splicing (del74-117) and (iii) a single amino-acid substitution (G715E). All mutations produce functional alterations that provide distinct explanations for their pathogenic phenotypes. M200fsX231 and del74-117 cause a loss of function of ClC-2 channels and are expected to lower the transmembrane chloride gradient essential for GABAergic inhibition. G715E alters voltage-dependent gating, which may cause membrane depolarization and hyperexcitability. 相似文献
123.
Credibility models in actuarial science deal with multiple short time series where each series represents claim amounts of different insurance groups. Commonly used credibility models imply shrinkage of group-specific estimates towards their average. In this paper we model the claim size yu in group i and at time t as the sum of three independent components: yit = μr + δi + ?it. The first component, μt = μt?1 + mt, represents time-varying levels that are common to all groups. The second component, δi, represents random group offsets that are the same in all periods, and the third component represents independent measurement errors. In this paper we show how to obtain forecasts from this model and we discuss the nature of the forecasts, with particular emphasis on shrinkage. We also assess the forecast improvements that can be expected from such a model. Finally, we discuss an extension of the above model which also allows the group offsets to change over time. We assume that the offsets for different groups follow independent random walks. 相似文献
124.
Römer W Berland L Chambon V Gaus K Windschiegl B Tenza D Aly MR Fraisier V Florent JC Perrais D Lamaze C Raposo G Steinem C Sens P Bassereau P Johannes L 《Nature》2007,450(7170):670-675
Clathrin seems to be dispensable for some endocytic processes and, in several instances, no cytosolic coat protein complexes could be detected at sites of membrane invagination. Hence, new principles must in these cases be invoked to account for the mechanical force driving membrane shape changes. Here we show that the Gb3 (glycolipid)-binding B-subunit of bacterial Shiga toxin induces narrow tubular membrane invaginations in human and mouse cells and model membranes. In cells, tubule occurrence increases on energy depletion and inhibition of dynamin or actin functions. Our data thus demonstrate that active cellular processes are needed for tubule scission rather than tubule formation. We conclude that the B-subunit induces lipid reorganization that favours negative membrane curvature, which drives the formation of inward membrane tubules. Our findings support a model in which the lateral growth of B-subunit-Gb3 microdomains is limited by the invagination process, which itself is regulated by membrane tension. The physical principles underlying this basic cargo-induced membrane uptake may also be relevant to other internalization processes, creating a rationale for conceptualizing the perplexing diversity of endocytic routes. 相似文献