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101.
Identification of the gene that, when mutated, causes the human obesity syndrome BBS4 总被引:21,自引:0,他引:21
Mykytyn K Braun T Carmi R Haider NB Searby CC Shastri M Beck G Wright AF Iannaccone A Elbedour K Riise R Baldi A Raas-Rothschild A Gorman SW Duhl DM Jacobson SG Casavant T Stone EM Sheffield VC 《Nature genetics》2001,28(2):188-191
Bardet-Biedl syndrome (BBS, MIM 209900) is a heterogeneous autosomal recessive disorder characterized by obesity, pigmentary retinopathy, polydactyly, renal malformations, mental retardation, and hypogenitalism. The disorder is also associated with diabetes mellitus, hypertension, and congenital heart disease. Six distinct BBS loci map to 11q13 (BBS1), 16q21 (BBS2), 3p13-p12 (BBS3), 15q22.3-q23 (BBS4), 2q31 (BBS5), and 20p12 (BBS6). Although BBS is rare in the general population (<1/100,000), there is considerable interest in identifying the genes causing BBS because components of the phenotype, such as obesity and diabetes, are common. We and others have demonstrated that BBS6 is caused by mutations in the gene MKKS (refs. 12,13), mutation of which also causes McKusick-Kaufman syndrome (hydrometrocolpos, post-axial polydactyly, and congenital heart defects). MKKS has sequence homology to the alpha subunit of a prokaryotic chaperonin in the thermosome Thermoplasma acidophilum. We recently identified a novel gene that causes BBS2. The BBS2 protein has no significant similarity to other chaperonins or known proteins. Here we report the positional cloning and identification of mutations in BBS patients in a novel gene designated BBS4. 相似文献
102.
Regulation of T-cell activity is dependent on antigen-independent co-stimulatory signals provided by the disulphide-linked homodimeric T-cell surface receptors, CD28 and CTLA-4 (ref. 1). Engagement of CD28 with B7-1 and B7-2 ligands on antigen-presenting cells (APCs) provides a stimulatory signal for T-cell activation, whereas subsequent engagement of CTLA-4 with these same ligands results in attenuation of the response. Given their central function in immune modulation, CTLA-4- and CD28-associated signalling pathways are primary therapeutic targets for preventing autoimmune disease, graft versus host disease, graft rejection and promoting tumour immunity. However, little is known about the cell-surface organization of these receptor/ligand complexes and the structural basis for signal transduction. Here we report the 3.2-A resolution structure of the complex between the disulphide-linked homodimer of human CTLA-4 and the receptor-binding domain of human B7-2. The unusual dimerization properties of both CTLA-4 and B7-2 place their respective ligand-binding sites distal to the dimer interface in each molecule and promote the formation of an alternating arrangement of bivalent CTLA-4 and B7-2 dimers that extends throughout the crystal. Direct observation of this CTLA-4/B7-2 network provides a model for the periodic organization of these molecules within the immunological synapse and suggests a distinct mechanism for signalling by dimeric cell-surface receptors. 相似文献
103.
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein 总被引:22,自引:0,他引:22
Watts GD Wymer J Kovach MJ Mehta SG Mumm S Darvish D Pestronk A Whyte MP Kimonis VE 《Nature genetics》2004,36(4):377-381
Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) is a dominant progressive disorder that maps to chromosome 9p21.1-p12. We investigated 13 families with IBMPFD linked to chromosome 9 using a candidate-gene approach. We found six missense mutations in the gene encoding valosin-containing protein (VCP, a member of the AAA-ATPase superfamily) exclusively in all 61 affected individuals. Haplotype analysis indicated that descent from two founders in two separate North American kindreds accounted for IBMPFD in approximately 50% of affected families. VCP is associated with a variety of cellular activities, including cell cycle control, membrane fusion and the ubiquitin-proteasome degradation pathway. Identification of VCP as causing IBMPFD has important implications for other inclusion-body diseases, including myopathies, dementias and Paget disease of bone (PDB), as it may define a new common pathological ubiquitin-based pathway. 相似文献
104.
From 1979 to 2001, temperatures observed globally by the mid-tropospheric channel of the satellite-borne Microwave Sounding Unit (MSU channel 2), as well as the inferred temperatures in the lower troposphere, show only small warming trends of less than 0.1 K per decade (refs 1-3). Surface temperatures based on in situ observations however, exhibit a larger warming of approximately 0.17 K per decade (refs 4, 5), and global climate models forced by combined anthropogenic and natural factors project an increase in tropospheric temperatures that is somewhat larger than the surface temperature increase. Here we show that trends in MSU channel 2 temperatures are weak because the instrument partly records stratospheric temperatures whose large cooling trend offsets the contributions of tropospheric warming. We quantify the stratospheric contribution to MSU channel 2 temperatures using MSU channel 4, which records only stratospheric temperatures. The resulting trend of reconstructed tropospheric temperatures from satellite data is physically consistent with the observed surface temperature trend. For the tropics, the tropospheric warming is approximately 1.6 times the surface warming, as expected for a moist adiabatic lapse rate. 相似文献
105.
To test the hypothesis that the human genome project will uncover many genes not previously discovered by sequencing of expressed sequence tags (ESTs), we designed and produced a set of microarrays using probes based on open reading frames (ORFs) in 350 Mb of finished and draft human sequence. Our approach aims to identify all genes directly from genomic sequence by querying gene expression. We analysed genomic sequence with a suite of ORF prediction programs, selected approximately one ORF per gene, amplified the ORFs from genomic DNA and arrayed the amplicons onto treated glass slides. Of the first 10,000 arrayed ORFs, 31% are completely novel and 29% are similar, but not identical, to sequences in public databases. Approximately one-half of these are expressed in the tissues we queried by microarray. Subsequent verification by other techniques confirmed expression of several of the novel genes. Expressed sequence tags (ESTs) have yielded vast amounts of data, but our results indicate that many genes in the human genome will only be found by genomic sequencing. 相似文献
106.
有些文本缺少字符集信息,因而阻碍了字符信息的正确解析.为了获得字符集信息可以根据文本中字符信息的统计特征以及各种字符集之同的差异来识别出文本的字符集.集成的字符集检测方法通过综合应用编码模式检测方法、字符分布方法和双字符序列检测方法来检测字符集.它根据算法复杂度和每种算法的准确率来调度算法.使得在用一种方法不能确定字符集的情况下利用其它方法来检测出字符集实验结果表明:集成的字符检测技术具有较高的准确率.集成的字符检测方法在某些情况下通过适度增加一些时间来获得较高的精度. 相似文献
107.
108.
Crow YJ Hayward BE Parmar R Robins P Leitch A Ali M Black DN van Bokhoven H Brunner HG Hamel BC Corry PC Cowan FM Frints SG Klepper J Livingston JH Lynch SA Massey RF Meritet JF Michaud JL Ponsot G Voit T Lebon P Bonthron DT Jackson AP Barnes DE Lindahl T 《Nature genetics》2006,38(8):917-920
Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response. 相似文献
109.
Delneri D Hoyle DC Gkargkas K Cross EJ Rash B Zeef L Leong HS Davey HM Hayes A Kell DB Griffith GW Oliver SG 《Nature genetics》2008,40(1):113-117
Using competition experiments in continuous cultures grown in different nutrient environments (glucose limited, ammonium limited, phosphate limited and white grape juice), we identified genes that show haploinsufficiency phenotypes (reduced growth rate when hemizygous) or haploproficiency phenotypes (increased growth rate when hemizygous). Haploproficient genes (815, 1,194, 733 and 654 in glucose-limited, ammonium-limited, phosphate-limited and white grape juice environments, respectively) frequently show that phenotype in a specific environmental context. For instance, genes encoding components of the ubiquitination pathway or the proteasome show haploproficiency in nitrogen-limited conditions where protein conservation may be beneficial. Haploinsufficiency is more likely to be observed in all environments, as is the case with genes determining polar growth of the cell. Haploproficient genes seem randomly distributed in the genome, whereas haploinsufficient genes (685, 765, 1,277 and 217 in glucose-limited, ammonium-limited, phosphate-limited and white grape juice environments, respectively) are over-represented on chromosome III. This chromosome determines a yeast's mating type, and the concentration of haploinsufficient genes there may be a mechanism to prevent its loss. 相似文献
110.
Martin MP Qi Y Gao X Yamada E Martin JN Pereyra F Colombo S Brown EE Shupert WL Phair J Goedert JJ Buchbinder S Kirk GD Telenti A Connors M O'Brien SJ Walker BD Parham P Deeks SG McVicar DW Carrington M 《Nature genetics》2007,39(6):733-740
Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)+ individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection. 相似文献