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PNPLA1 mutations cause autosomal recessive congenital ichthyosis in golden retriever dogs and humans
Grall A Guaguère E Planchais S Grond S Bourrat E Hausser I Hitte C Le Gallo M Derbois C Kim GJ Lagoutte L Degorce-Rubiales F Radner FP Thomas A Küry S Bensignor E Fontaine J Pin D Zimmermann R Zechner R Lathrop M Galibert F André C Fischer J 《Nature genetics》2012,44(2):140-147
Ichthyoses comprise a heterogeneous group of genodermatoses characterized by abnormal desquamation over the whole body, for which the genetic causes of several human forms remain unknown. We used a spontaneous dog model in the golden retriever breed, which is affected by a lamellar ichthyosis resembling human autosomal recessive congenital ichthyoses (ARCI), to carry out a genome-wide association study. We identified a homozygous insertion-deletion (indel) mutation in PNPLA1 that leads to a premature stop codon in all affected golden retriever dogs. We subsequently found one missense and one nonsense mutation in the catalytic domain of human PNPLA1 in six individuals with ARCI from two families. Further experiments highlighted the importance of PNPLA1 in the formation of the epidermal lipid barrier. This study identifies a new gene involved in human ichthyoses and provides insights into the localization and function of this yet uncharacterized member of the PNPLA protein family. 相似文献
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Based on a sample of 17 adult specimens of Sceloporus horridus taken near Autlan, Jalisco, Mexico in May 1974 just before and just after the first rainfall of the year, we present the first published data on the food habits of this lizard. Important prey item taxa were Homoptera, Coleoptera, Hymenoptera, Orthoptera, and Isoptera. The absence of Homoptera and Orthoptera, and the concomitant greater relative importance of Isoptera and Hymenoptera in the diet after the rain than before indicates opportunistic feeding by S. horridus. Our data suggest that reproduction in this lizard is probably initiated soon after the first rains in late spring. 相似文献
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Tschöp M Castañeda TR Joost HG Thöne-Reineke C Ortmann S Klaus S Hagan MM Chandler PC Oswald KD Benoit SC Seeley RJ Kinzig KP Moran TH Beck-sickinger AG Koglin N Rodgers RJ Blundell JE Ishii Y Beattie AH Holch P Allison DB Raun K Madsen K Wulff BS Stidsen CE Birringer M Kreuzer OJ Schindler M Arndt K Rudolf K Mark M Deng XY Whitcomb DC Halem H Taylor J Dong J Datta R Culler M Craney S Flora D Smiley D Heiman ML Withcomb DC 《Nature》2004,430(6996):1 p following 165; discussion 2 p following 165
Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36. 相似文献
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In this paper we consider a specific model of membrane systems, i. e. membrane systems with attributes. In these systems, the information is placed at the membranes in form of attributes, no objects are considered inside the membranes except for other membranes. The membrane system with attributes evolves according to rules that compute new values for the attributes from the attributes assigned to the membranes involved in the rule. The model of membrane systems with attributes allows us to specify business transactions in a precise way and to simulate different models for such transactions with a suitable tool for membrane systems with attributes. 相似文献
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In this paper we consider a specific model of membrane systems, i. e. membrane systems with attributes. In these systems, the information is placed at the membranes in form of attributes, no objects are considered inside the membranes except for other membranes. The membrane system with attributes evolves according to rules that compute new values for the attributes from the attributes assigned to the membranes involved in the rule. The model of membrane systems with attributes allows us to specify business transactions in a precise way and to simulate different models for such transactions with a suitable tool for membrane systems with attributes. 相似文献
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Summary The measurement of meson masses in the cosmic radiation with a slowly expanding wilson chambre indicates mesons of different masses. There are at least two different masses, one between 100m
0 and 200m
0, and the other exceeding 200m
0. 相似文献
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M Dühren-von Minden R Übelhart D Schneider T Wossning MP Bach M Buchner D Hofmann E Surova M Follo F Köhler H Wardemann K Zirlik H Veelken H Jumaa 《Nature》2012,489(7415):309-312
B-cell antigen receptor (BCR) expression is an important feature of chronic lymphocytic leukaemia (CLL), one of the most prevalent B-cell neoplasias in Western countries. The presence of stereotyped and quasi-identical BCRs in different CLL patients suggests that recognition of specific antigens might drive CLL pathogenesis. Here we show that, in contrast to other B-cell neoplasias, CLL-derived BCRs induce antigen-independent cell-autonomous signalling, which is dependent on the heavy-chain complementarity-determining region (HCDR3) and an internal epitope of the BCR. Indeed, transferring the HCDR3 of a CLL-derived BCR provides autonomous signalling capacity to a non-autonomously active BCR, whereas mutations in the internal epitope abolish this capacity. Because BCR expression was required for the binding of secreted CLL-derived BCRs to target cells, and mutations in the internal epitope reduced this binding, our results indicate a new model for CLL pathogenesis, with cell-autonomous antigen-independent signalling as a crucial pathogenic mechanism. 相似文献
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Helicases are a ubiquitous class of enzymes involved in nearly all aspects of DNA and RNA metabolism. Despite recent progress in understanding their mechanism of action, limited resolution has left inaccessible the detailed mechanisms by which these enzymes couple the rearrangement of nucleic acid structures to the binding and hydrolysis of ATP. Observing individual mechanistic cycles of these motor proteins is central to understanding their cellular functions. Here we follow in real time, at a resolution of two base pairs and 20 ms, the RNA translocation and unwinding cycles of a hepatitis C virus helicase (NS3) monomer. NS3 is a representative superfamily-2 helicase essential for viral replication, and therefore a potentially important drug target. We show that the cyclic movement of NS3 is coordinated by ATP in discrete steps of 11 +/- 3 base pairs, and that actual unwinding occurs in rapid smaller substeps of 3.6 +/- 1.3 base pairs, also triggered by ATP binding, indicating that NS3 might move like an inchworm. This ATP-coupling mechanism is likely to be applicable to other non-hexameric helicases involved in many essential cellular functions. The assay developed here should be useful in investigating a broad range of nucleic acid translocation motors. 相似文献
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The conserved protein DCN-1/Dcn1p is required for cullin neddylation in C. elegans and S. cerevisiae
Kurz T Ozlü N Rudolf F O'Rourke SM Luke B Hofmann K Hyman AA Bowerman B Peter M 《Nature》2005,435(7046):1257-1261
SCF-type E3 ubiquitin ligases are multi-protein complexes required for polyubiquitination and subsequent degradation of target proteins by the 26S proteasome. Cullins, together with the RING-finger protein Rbx1, form the catalytic core of the ligase, and recruit the substrate-recognition module. Cycles of covalent modification of cullins by the ubiquitin-like molecule Nedd8 (neddylation) and removal of Nedd8 by the COP9 signalosome (deneddylation) positively regulate E3 ligase activity. Here we report the identification and analysis of a widely conserved protein that is required for cullin neddylation in the nematode Caenorhabditis elegans and the yeast Saccharomyces cerevisiae. C. elegans DCN-1 and S. cerevisiae Dcn1p (defective in cullin neddylation) are characterized by a novel UBA-like ubiquitin-binding domain and a DUF298 domain of unknown function. Consistent with their requirements for neddylation, DCN-1 and Dcn1p directly bind Nedd8 and physically associate with cullins in both species. Moreover, overexpression of Dcn1p in yeast results in the accumulation of Nedd8-modified cullin Cdc53p. Both in vivo and in vitro experiments indicate that Dcn1p does not inhibit deneddylation of Cdc53p by the COP9 signalosome, but greatly increases the kinetics of the neddylation reaction. 相似文献