ALBERT

Description: Entry into anaphase and exit from mitosis depend on a ubiquitin-protein ligase complex called the anaphase-promoting complex (APC) or cyclosome. At least 12 different subunits were detected in the purified particle from budding yeast, including the previously identified proteins Apc1p, Cdc16p, Cdc23p, Cdc26p, and Cdc27p. Five additional subunits purified in low nanogram amounts were identified by tandem mass spectrometric sequencing. Apc2p, Apc5p, and the RING-finger protein Apc11p are conserved from yeast to humans. Apc2p is similar to the cullin Cdc53p, which is a subunit of the ubiquitin-protein ligase complex SCFCdc4 required for the initiation of DNA replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zachariae, W -- Shevchenko, A -- Andrews, P D -- Ciosk, R -- Galova, M -- Stark, M J -- Mann, M -- Nasmyth, K -- New York, N.Y. -- Science. 1998 Feb 20;279(5354):1216-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9469814" target="_blank"〉PubMed〈/a〉

Description: We present a draft genome sequence of the platypus, Ornithorhynchus anatinus. This monotreme exhibits a fascinating combination of reptilian and mammalian characters. For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles. Analysis of the first monotreme genome aligned these features with genetic innovations. We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology. Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified. Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803040/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2803040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Wesley C -- Hillier, LaDeana W -- Marshall Graves, Jennifer A -- Birney, Ewan -- Ponting, Chris P -- Grutzner, Frank -- Belov, Katherine -- Miller, Webb -- Clarke, Laura -- Chinwalla, Asif T -- Yang, Shiaw-Pyng -- Heger, Andreas -- Locke, Devin P -- Miethke, Pat -- Waters, Paul D -- Veyrunes, Frederic -- Fulton, Lucinda -- Fulton, Bob -- Graves, Tina -- Wallis, John -- Puente, Xose S -- Lopez-Otin, Carlos -- Ordonez, Gonzalo R -- Eichler, Evan E -- Chen, Lin -- Cheng, Ze -- Deakin, Janine E -- Alsop, Amber -- Thompson, Katherine -- Kirby, Patrick -- Papenfuss, Anthony T -- Wakefield, Matthew J -- Olender, Tsviya -- Lancet, Doron -- Huttley, Gavin A -- Smit, Arian F A -- Pask, Andrew -- Temple-Smith, Peter -- Batzer, Mark A -- Walker, Jerilyn A -- Konkel, Miriam K -- Harris, Robert S -- Whittington, Camilla M -- Wong, Emily S W -- Gemmell, Neil J -- Buschiazzo, Emmanuel -- Vargas Jentzsch, Iris M -- Merkel, Angelika -- Schmitz, Juergen -- Zemann, Anja -- Churakov, Gennady -- Kriegs, Jan Ole -- Brosius, Juergen -- Murchison, Elizabeth P -- Sachidanandam, Ravi -- Smith, Carly -- Hannon, Gregory J -- Tsend-Ayush, Enkhjargal -- McMillan, Daniel -- Attenborough, Rosalind -- Rens, Willem -- Ferguson-Smith, Malcolm -- Lefevre, Christophe M -- Sharp, Julie A -- Nicholas, Kevin R -- Ray, David A -- Kube, Michael -- Reinhardt, Richard -- Pringle, Thomas H -- Taylor, James -- Jones, Russell C -- Nixon, Brett -- Dacheux, Jean-Louis -- Niwa, Hitoshi -- Sekita, Yoko -- Huang, Xiaoqiu -- Stark, Alexander -- Kheradpour, Pouya -- Kellis, Manolis -- Flicek, Paul -- Chen, Yuan -- Webber, Caleb -- Hardison, Ross -- Nelson, Joanne -- Hallsworth-Pepin, Kym -- Delehaunty, Kim -- Markovic, Chris -- Minx, Pat -- Feng, Yucheng -- Kremitzki, Colin -- Mitreva, Makedonka -- Glasscock, Jarret -- Wylie, Todd -- Wohldmann, Patricia -- Thiru, Prathapan -- Nhan, Michael N -- Pohl, Craig S -- Smith, Scott M -- Hou, Shunfeng -- Nefedov, Mikhail -- de Jong, Pieter J -- Renfree, Marilyn B -- Mardis, Elaine R -- Wilson, Richard K -- 062023/Wellcome Trust/United Kingdom -- HG002238/HG/NHGRI NIH HHS/ -- MC_U137761446/Medical Research Council/United Kingdom -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA013106-37/CA/NCI NIH HHS/ -- R01 GM59290/GM/NIGMS NIH HHS/ -- R01 HG002939/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG004037-02/HG/NHGRI NIH HHS/ -- R01HG02385/HG/NHGRI NIH HHS/ -- Medical Research Council/United Kingdom -- England -- Nature. 2008 May 8;453(7192):175-83. doi: 10.1038/nature06936.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Sequencing Center, Washington University School of Medicine, Campus Box 8501, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. wwarren@wustl.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18464734" target="_blank"〉PubMed〈/a〉

Description: The human body is composed of diverse cell types with distinct functions. Although it is known that lineage specification depends on cell-specific gene expression, which in turn is driven by promoters, enhancers, insulators and other cis-regulatory DNA sequences for each gene, the relative roles of these regulatory elements in this process are not clear. We have previously developed a chromatin-immunoprecipitation-based microarray method (ChIP-chip) to locate promoters, enhancers and insulators in the human genome. Here we use the same approach to identify these elements in multiple cell types and investigate their roles in cell-type-specific gene expression. We observed that the chromatin state at promoters and CTCF-binding at insulators is largely invariant across diverse cell types. In contrast, enhancers are marked with highly cell-type-specific histone modification patterns, strongly correlate to cell-type-specific gene expression programs on a global scale, and are functionally active in a cell-type-specific manner. Our results define over 55,000 potential transcriptional enhancers in the human genome, significantly expanding the current catalogue of human enhancers and highlighting the role of these elements in cell-type-specific gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910248/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2910248/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heintzman, Nathaniel D -- Hon, Gary C -- Hawkins, R David -- Kheradpour, Pouya -- Stark, Alexander -- Harp, Lindsey F -- Ye, Zhen -- Lee, Leonard K -- Stuart, Rhona K -- Ching, Christina W -- Ching, Keith A -- Antosiewicz-Bourget, Jessica E -- Liu, Hui -- Zhang, Xinmin -- Green, Roland D -- Lobanenkov, Victor V -- Stewart, Ron -- Thomson, James A -- Crawford, Gregory E -- Kellis, Manolis -- Ren, Bing -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG004037-02/HG/NHGRI NIH HHS/ -- U01 HG003151/HG/NHGRI NIH HHS/ -- U01 HG003151-01/HG/NHGRI NIH HHS/ -- U01 HG003151-01S1/HG/NHGRI NIH HHS/ -- U01 HG003151-02/HG/NHGRI NIH HHS/ -- U01 HG003151-03/HG/NHGRI NIH HHS/ -- U01 HG003151-03S1/HG/NHGRI NIH HHS/ -- U01 HG003151-03S2/HG/NHGRI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2009 May 7;459(7243):108-12. doi: 10.1038/nature07829. Epub 2009 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Institute for Cancer Research, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, California 92093-0653, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19295514" target="_blank"〉PubMed〈/a〉

Description: Once all chromosomes are connected to the mitotic spindle (bioriented), anaphase is initiated by the protein ubiquitylation activity of the anaphase-promoting complex/cyclosome (APC/C) and its coactivator Cdc20 (APC/C(Cdc20)). Before chromosome biorientation, anaphase is delayed by a mitotic checkpoint complex (MCC) that inhibits APC/C(Cdc20). We used single-particle electron microscopy to obtain three-dimensional models of human APC/C in various functional states: bound to MCC, to Cdc20, or to neither (apo-APC/C). These experiments revealed that MCC associates with the Cdc20 binding site on APC/C, locks the otherwise flexible APC/C in a "closed" state, and prevents binding and ubiquitylation of a wide range of different APC/C substrates. These observations clarify the structural basis for the inhibition of APC/C by spindle checkpoint proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989460/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989460/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herzog, Franz -- Primorac, Ivana -- Dube, Prakash -- Lenart, Peter -- Sander, Bjorn -- Mechtler, Karl -- Stark, Holger -- Peters, Jan-Michael -- F 3407/Austrian Science Fund FWF/Austria -- New York, N.Y. -- Science. 2009 Mar 13;323(5920):1477-81. doi: 10.1126/science.1163300.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19286556" target="_blank"〉PubMed〈/a〉

Description: Chromosome segregation and cell division are essential, highly ordered processes that depend on numerous protein complexes. Results from recent RNA interference screens indicate that the identity and composition of these protein complexes is incompletely understood. Using gene tagging on bacterial artificial chromosomes, protein localization, and tandem-affinity purification-mass spectrometry, the MitoCheck consortium has analyzed about 100 human protein complexes, many of which had not or had only incompletely been characterized. This work has led to the discovery of previously unknown, evolutionarily conserved subunits of the anaphase-promoting complex and the gamma-tubulin ring complex--large complexes that are essential for spindle assembly and chromosome segregation. The approaches we describe here are generally applicable to high-throughput follow-up analyses of phenotypic screens in mammalian cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989461/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2989461/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hutchins, James R A -- Toyoda, Yusuke -- Hegemann, Bjorn -- Poser, Ina -- Heriche, Jean-Karim -- Sykora, Martina M -- Augsburg, Martina -- Hudecz, Otto -- Buschhorn, Bettina A -- Bulkescher, Jutta -- Conrad, Christian -- Comartin, David -- Schleiffer, Alexander -- Sarov, Mihail -- Pozniakovsky, Andrei -- Slabicki, Mikolaj Michal -- Schloissnig, Siegfried -- Steinmacher, Ines -- Leuschner, Marit -- Ssykor, Andrea -- Lawo, Steffen -- Pelletier, Laurence -- Stark, Holger -- Nasmyth, Kim -- Ellenberg, Jan -- Durbin, Richard -- Buchholz, Frank -- Mechtler, Karl -- Hyman, Anthony A -- Peters, Jan-Michael -- F 3407/Austrian Science Fund FWF/Austria -- New York, N.Y. -- Science. 2010 Apr 30;328(5978):593-9. doi: 10.1126/science.1181348. Epub 2010 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology (IMP), Dr. Bohr-Gasse 7, A-1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20360068" target="_blank"〉PubMed〈/a〉

Description: Signal transducers and activators of transcription (STATs) enhance transcription of specific genes in response to cytokines and growth factors. STAT1 is also required for efficient constitutive expression of the caspases Ice, Cpp32, and Ich-1 in human fibroblasts. As a consequence, STAT1-null cells are resistant to apoptosis by tumor necrosis factor alpha (TNF-alpha). Reintroduction of STAT1alpha restored both TNF-alpha-induced apoptosis and the expression of Ice, Cpp32, and Ich-1. Variant STAT1 proteins carrying point mutations that inactivate domains required for STAT dimer formation nevertheless restored protease expression and sensitivity to apoptosis, indicating that the functions of STAT1 required for these activities are different from those that mediate induced gene expression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kumar, A -- Commane, M -- Flickinger, T W -- Horvath, C M -- Stark, G R -- P01 CA62220/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 1997 Nov 28;278(5343):1630-2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9374464" target="_blank"〉PubMed〈/a〉

Description: The splicing factor SF3b is a multiprotein complex essential for the accurate excision of introns from pre-messenger RNA. As an integral component of the U2 small nuclear ribonucleoprotein (snRNP) and the U11/U12 di-snRNP, SF3b is involved in the recognition of the pre-messenger RNA's branch site within the major and minor spliceosomes. We have determined the three-dimensional structure of the human SF3b complex by single-particle electron cryomicroscopy at a resolution of less than 10 angstroms, allowing identification of protein domains with known structural folds. The best fit of a modeled RNA-recognition motif indicates that the protein p14 is located in the central cavity of the complex. The 22 tandem helical repeats of the protein SF3b155 are located in the outer shell of the complex enclosing p14.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Golas, Monika M -- Sander, Bjoern -- Will, Cindy L -- Luhrmann, Reinhard -- Stark, Holger -- New York, N.Y. -- Science. 2003 May 9;300(5621):980-4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/12738865" target="_blank"〉PubMed〈/a〉

Description: The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering approximately 4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for approximately 60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207357/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3207357/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindblad-Toh, Kerstin -- Garber, Manuel -- Zuk, Or -- Lin, Michael F -- Parker, Brian J -- Washietl, Stefan -- Kheradpour, Pouya -- Ernst, Jason -- Jordan, Gregory -- Mauceli, Evan -- Ward, Lucas D -- Lowe, Craig B -- Holloway, Alisha K -- Clamp, Michele -- Gnerre, Sante -- Alfoldi, Jessica -- Beal, Kathryn -- Chang, Jean -- Clawson, Hiram -- Cuff, James -- Di Palma, Federica -- Fitzgerald, Stephen -- Flicek, Paul -- Guttman, Mitchell -- Hubisz, Melissa J -- Jaffe, David B -- Jungreis, Irwin -- Kent, W James -- Kostka, Dennis -- Lara, Marcia -- Martins, Andre L -- Massingham, Tim -- Moltke, Ida -- Raney, Brian J -- Rasmussen, Matthew D -- Robinson, Jim -- Stark, Alexander -- Vilella, Albert J -- Wen, Jiayu -- Xie, Xiaohui -- Zody, Michael C -- Broad Institute Sequencing Platform and Whole Genome Assembly Team -- Baldwin, Jen -- Bloom, Toby -- Chin, Chee Whye -- Heiman, Dave -- Nicol, Robert -- Nusbaum, Chad -- Young, Sarah -- Wilkinson, Jane -- Worley, Kim C -- Kovar, Christie L -- Muzny, Donna M -- Gibbs, Richard A -- Baylor College of Medicine Human Genome Sequencing Center Sequencing Team -- Cree, Andrew -- Dihn, Huyen H -- Fowler, Gerald -- Jhangiani, Shalili -- Joshi, Vandita -- Lee, Sandra -- Lewis, Lora R -- Nazareth, Lynne V -- Okwuonu, Geoffrey -- Santibanez, Jireh -- Warren, Wesley C -- Mardis, Elaine R -- Weinstock, George M -- Wilson, Richard K -- Genome Institute at Washington University -- Delehaunty, Kim -- Dooling, David -- Fronik, Catrina -- Fulton, Lucinda -- Fulton, Bob -- Graves, Tina -- Minx, Patrick -- Sodergren, Erica -- Birney, Ewan -- Margulies, Elliott H -- Herrero, Javier -- Green, Eric D -- Haussler, David -- Siepel, Adam -- Goldman, Nick -- Pollard, Katherine S -- Pedersen, Jakob S -- Lander, Eric S -- Kellis, Manolis -- 095908/Wellcome Trust/United Kingdom -- GM82901/GM/NIGMS NIH HHS/ -- R01 HG003474/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-09/HG/NHGRI NIH HHS/ -- U54 HG003273/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Oct 12;478(7370):476-82. doi: 10.1038/nature10530.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. kersli@broadinstitute.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993624" target="_blank"〉PubMed〈/a〉

Description: There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using approximately 170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of approximately 0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564953/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564953/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Jian -- Loos, Ruth J F -- Powell, Joseph E -- Medland, Sarah E -- Speliotes, Elizabeth K -- Chasman, Daniel I -- Rose, Lynda M -- Thorleifsson, Gudmar -- Steinthorsdottir, Valgerdur -- Magi, Reedik -- Waite, Lindsay -- Smith, Albert Vernon -- Yerges-Armstrong, Laura M -- Monda, Keri L -- Hadley, David -- Mahajan, Anubha -- Li, Guo -- Kapur, Karen -- Vitart, Veronique -- Huffman, Jennifer E -- Wang, Sophie R -- Palmer, Cameron -- Esko, Tonu -- Fischer, Krista -- Zhao, Jing Hua -- Demirkan, Ayse -- Isaacs, Aaron -- Feitosa, Mary F -- Luan, Jian'an -- Heard-Costa, Nancy L -- White, Charles -- Jackson, Anne U -- Preuss, Michael -- Ziegler, Andreas -- Eriksson, Joel -- Kutalik, Zoltan -- Frau, Francesca -- Nolte, Ilja M -- Van Vliet-Ostaptchouk, Jana V -- Hottenga, Jouke-Jan -- Jacobs, Kevin B -- Verweij, Niek -- Goel, Anuj -- Medina-Gomez, Carolina -- Estrada, Karol -- Bragg-Gresham, Jennifer Lynn -- Sanna, Serena -- Sidore, Carlo -- Tyrer, Jonathan -- Teumer, Alexander -- Prokopenko, Inga -- Mangino, Massimo -- Lindgren, Cecilia M -- Assimes, Themistocles L -- Shuldiner, Alan R -- Hui, Jennie -- Beilby, John P -- McArdle, Wendy L -- Hall, Per -- Haritunians, Talin -- Zgaga, Lina -- Kolcic, Ivana -- Polasek, Ozren -- Zemunik, Tatijana -- Oostra, Ben A -- Junttila, M Juhani -- Gronberg, Henrik -- Schreiber, Stefan -- Peters, Annette -- Hicks, Andrew A -- Stephens, Jonathan -- Foad, Nicola S -- Laitinen, Jaana -- Pouta, Anneli -- Kaakinen, Marika -- Willemsen, Gonneke -- Vink, Jacqueline M -- Wild, Sarah H -- Navis, Gerjan -- Asselbergs, Folkert W -- Homuth, Georg -- John, Ulrich -- Iribarren, Carlos -- Harris, Tamara -- Launer, Lenore -- Gudnason, Vilmundur -- O'Connell, Jeffrey R -- Boerwinkle, Eric -- Cadby, Gemma -- Palmer, Lyle J -- James, Alan L -- Musk, Arthur W -- Ingelsson, Erik -- Psaty, Bruce M -- Beckmann, Jacques S -- Waeber, Gerard -- Vollenweider, Peter -- Hayward, Caroline -- Wright, Alan F -- Rudan, Igor -- Groop, Leif C -- Metspalu, Andres -- Khaw, Kay Tee -- van Duijn, Cornelia M -- Borecki, Ingrid B -- Province, Michael A -- Wareham, Nicholas J -- Tardif, Jean-Claude -- Huikuri, Heikki V -- Cupples, L Adrienne -- Atwood, Larry D -- Fox, Caroline S -- Boehnke, Michael -- Collins, Francis S -- Mohlke, Karen L -- Erdmann, Jeanette -- Schunkert, Heribert -- Hengstenberg, Christian -- Stark, Klaus -- Lorentzon, Mattias -- Ohlsson, Claes -- Cusi, Daniele -- Staessen, Jan A -- Van der Klauw, Melanie M -- Pramstaller, Peter P -- Kathiresan, Sekar -- Jolley, Jennifer D -- Ripatti, Samuli -- Jarvelin, Marjo-Riitta -- de Geus, Eco J C -- Boomsma, Dorret I -- Penninx, Brenda -- Wilson, James F -- Campbell, Harry -- Chanock, Stephen J -- van der Harst, Pim -- Hamsten, Anders -- Watkins, Hugh -- Hofman, Albert -- Witteman, Jacqueline C -- Zillikens, M Carola -- Uitterlinden, Andre G -- Rivadeneira, Fernando -- Kiemeney, Lambertus A -- Vermeulen, Sita H -- Abecasis, Goncalo R -- Schlessinger, David -- Schipf, Sabine -- Stumvoll, Michael -- Tonjes, Anke -- Spector, Tim D -- North, Kari E -- Lettre, Guillaume -- McCarthy, Mark I -- Berndt, Sonja I -- Heath, Andrew C -- Madden, Pamela A F -- Nyholt, Dale R -- Montgomery, Grant W -- Martin, Nicholas G -- McKnight, Barbara -- Strachan, David P -- Hill, William G -- Snieder, Harold -- Ridker, Paul M -- Thorsteinsdottir, Unnur -- Stefansson, Kari -- Frayling, Timothy M -- Hirschhorn, Joel N -- Goddard, Michael E -- Visscher, Peter M -- 090532/Wellcome Trust/United Kingdom -- 14136/Cancer Research UK/United Kingdom -- AA014041/AA/NIAAA NIH HHS/ -- AA07535/AA/NIAAA NIH HHS/ -- AA10248/AA/NIAAA NIH HHS/ -- AA13320/AA/NIAAA NIH HHS/ -- AA13321/AA/NIAAA NIH HHS/ -- AA13326/AA/NIAAA NIH HHS/ -- CZB/4/710/Chief Scientist Office/United Kingdom -- DA12854/DA/NIDA NIH HHS/ -- F32 AR059469/AR/NIAMS NIH HHS/ -- F32 DK079466/DK/NIDDK NIH HHS/ -- G0601261/Medical Research Council/United Kingdom -- G1000143/Medical Research Council/United Kingdom -- GM057091/GM/NIGMS NIH HHS/ -- HHSN268201100005C/HL/NHLBI NIH HHS/ -- HHSN268201100006C/HL/NHLBI NIH HHS/ -- HHSN268201100007C/HL/NHLBI NIH HHS/ -- HHSN268201100008C/HL/NHLBI NIH HHS/ -- HHSN268201100009C/HL/NHLBI NIH HHS/ -- HHSN268201100010C/HL/NHLBI NIH HHS/ -- HHSN268201100011C/HL/NHLBI NIH HHS/ -- HHSN268201100012C/HL/NHLBI NIH HHS/ -- K05 AA017688/AA/NIAAA NIH HHS/ -- K23 DK080145/DK/NIDDK NIH HHS/ -- MC_PC_U127561128/Medical Research Council/United Kingdom -- MC_U106179471/Medical Research Council/United Kingdom -- MC_U127561128/Medical Research Council/United Kingdom -- N01 AG012100/AG/NIA NIH HHS/ -- N01 HC015103/HC/NHLBI NIH HHS/ -- N01 HC025195/HC/NHLBI NIH HHS/ -- N01 HC035129/HC/NHLBI NIH HHS/ -- N01 HC045133/HC/NHLBI NIH HHS/ -- N01 HC055222/HC/NHLBI NIH HHS/ -- N01 HC075150/HC/NHLBI NIH HHS/ -- N01 HC085079/HC/NHLBI NIH HHS/ -- N01 HG065403/HG/NHGRI NIH HHS/ -- N01HC85086/HL/NHLBI NIH HHS/ -- N02 HL64278/HL/NHLBI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- P30 DK072488/DK/NIDDK NIH HHS/ -- R01 AA007535/AA/NIAAA NIH HHS/ -- R01 AA013320/AA/NIAAA NIH HHS/ -- R01 AA013321/AA/NIAAA NIH HHS/ -- R01 AA013326/AA/NIAAA NIH HHS/ -- R01 AA014041/AA/NIAAA NIH HHS/ -- R01 AG015928/AG/NIA NIH HHS/ -- R01 AG020098/AG/NIA NIH HHS/ -- R01 AG023629/AG/NIA NIH HHS/ -- R01 AG027058/AG/NIA NIH HHS/ -- R01 DA012854/DA/NIDA NIH HHS/ -- R01 DK062370/DK/NIDDK NIH HHS/ -- R01 DK072193/DK/NIDDK NIH HHS/ -- R01 DK073490/DK/NIDDK NIH HHS/ -- R01 DK075681/DK/NIDDK NIH HHS/ -- R01 DK075787/DK/NIDDK NIH HHS/ -- R01 HG002651/HG/NHGRI NIH HHS/ -- R01 HL043851/HL/NHLBI NIH HHS/ -- R01 HL059367/HL/NHLBI NIH HHS/ -- R01 HL075366/HL/NHLBI NIH HHS/ -- R01 HL080295/HL/NHLBI NIH HHS/ -- R01 HL086694/HL/NHLBI NIH HHS/ -- R01 HL087641/HL/NHLBI NIH HHS/ -- R01 HL087647/HL/NHLBI NIH HHS/ -- R01 HL087652/HL/NHLBI NIH HHS/ -- R01 HL087676/HL/NHLBI NIH HHS/ -- R01 HL087679/HL/NHLBI NIH HHS/ -- R01 HL105756/HL/NHLBI NIH HHS/ -- R01 LM010098/LM/NLM NIH HHS/ -- R01 MH063706/MH/NIMH NIH HHS/ -- RL1 MH083268/MH/NIMH NIH HHS/ -- U01 DK062418/DK/NIDDK NIH HHS/ -- U01 HG004402/HG/NHGRI NIH HHS/ -- U01 HL054527/HL/NHLBI NIH HHS/ -- U01 HL069757/HL/NHLBI NIH HHS/ -- U01 HL072515/HL/NHLBI NIH HHS/ -- U01 HL084729/HL/NHLBI NIH HHS/ -- U01 HL084756/HL/NHLBI NIH HHS/ -- U54 RR020278/RR/NCRR NIH HHS/ -- UL1 RR033176/RR/NCRR NIH HHS/ -- Z01 HG000024-14/Intramural NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):267-72. doi: 10.1038/nature11401. Epub 2012 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Queensland Diamantina Institute, The University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22982992" target="_blank"〉PubMed〈/a〉

Description: Myocardial infarction, a leading cause of death in the Western world, usually occurs when the fibrous cap overlying an atherosclerotic plaque in a coronary artery ruptures. The resulting exposure of blood to the atherosclerotic material then triggers thrombus formation, which occludes the artery. The importance of genetic predisposition to coronary artery disease and myocardial infarction is best documented by the predictive value of a positive family history. Next-generation sequencing in families with several affected individuals has revolutionized mutation identification. Here we report the segregation of two private, heterozygous mutations in two functionally related genes, GUCY1A3 (p.Leu163Phefs*24) and CCT7 (p.Ser525Leu), in an extended myocardial infarction family. GUCY1A3 encodes the alpha1 subunit of soluble guanylyl cyclase (alpha1-sGC), and CCT7 encodes CCTeta, a member of the tailless complex polypeptide 1 ring complex, which, among other functions, stabilizes soluble guanylyl cyclase. After stimulation with nitric oxide, soluble guanylyl cyclase generates cGMP, which induces vasodilation and inhibits platelet activation. We demonstrate in vitro that mutations in both GUCY1A3 and CCT7 severely reduce alpha1-sGC as well as beta1-sGC protein content, and impair soluble guanylyl cyclase activity. Moreover, platelets from digenic mutation carriers contained less soluble guanylyl cyclase protein and consequently displayed reduced nitric-oxide-induced cGMP formation. Mice deficient in alpha1-sGC protein displayed accelerated thrombus formation in the microcirculation after local trauma. Starting with a severely affected family, we have identified a link between impaired soluble-guanylyl-cyclase-dependent nitric oxide signalling and myocardial infarction risk, possibly through accelerated thrombus formation. Reversing this defect may provide a new therapeutic target for reducing the risk of myocardial infarction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Erdmann, Jeanette -- Stark, Klaus -- Esslinger, Ulrike B -- Rumpf, Philipp Moritz -- Koesling, Doris -- de Wit, Cor -- Kaiser, Frank J -- Braunholz, Diana -- Medack, Anja -- Fischer, Marcus -- Zimmermann, Martina E -- Tennstedt, Stephanie -- Graf, Elisabeth -- Eck, Sebastian -- Aherrahrou, Zouhair -- Nahrstaedt, Janja -- Willenborg, Christina -- Bruse, Petra -- Braenne, Ingrid -- Nothen, Markus M -- Hofmann, Per -- Braund, Peter S -- Mergia, Evanthia -- Reinhard, Wibke -- Burgdorf, Christof -- Schreiber, Stefan -- Balmforth, Anthony J -- Hall, Alistair S -- Bertram, Lars -- Steinhagen-Thiessen, Elisabeth -- Li, Shu-Chen -- Marz, Winfried -- Reilly, Muredach -- Kathiresan, Sekar -- McPherson, Ruth -- Walter, Ulrich -- CARDIoGRAM -- Ott, Jurg -- Samani, Nilesh J -- Strom, Tim M -- Meitinger, Thomas -- Hengstenberg, Christian -- Schunkert, Heribert -- British Heart Foundation/United Kingdom -- England -- Nature. 2013 Dec 19;504(7480):432-6. doi: 10.1038/nature12722. Epub 2013 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [3]. ; 1] Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany [2] Department of Genetic Epidemiology, University of Regensburg, 93053 Regensburg, Germany [3]. ; 1] Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany [2] Institut National de la Sante et de la Recherche Medicale (INSERM), UMR-S937 Paris, France [3]. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany [3]. ; Department of Pharmacology and Toxicology, Ruhr-University Bochum, 44801 Bochum, Germany. ; 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [2] Institut fur Physiologie, Universitat zu Lubeck, 23562 Lubeck, Germany. ; 1] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany [2] Institut fur Humangenetik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Institut fur Humangenetik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany. ; Klinik und Poliklinik fur Innere Medizin II, Universitatsklinikum Regensburg, 93053 Regensburg, Germany. ; 1] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany [2] Institute of Human Genetics, Technische Universitat Munchen, 81675 Munchen, Germany. ; 1] Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, 23562 Lubeck, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Hamburg/Lubeck/Kiel, 23562 Lubeck, Germany. ; 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Department of Genomics, Research Center Life & Brain, University of Bonn, 53127 Bonn, Germany. ; 1] Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany [2] Division of Medical Genetics, University Hospital Basel and Department of Biomedicine, University of Basel, 4003 Basel, Switzerland. ; 1] Department of Cardiovascular Sciences, University of Leicester, Leicester LE1 7RH, UK [2] Leicester National Institute for Health Research Biomedical Research Unit in Cardiovascular Disease, Glenfield Hospital, Leicester LE1 7RH, UK. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, 80636 Munich, Germany. ; Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany. ; Institute of Clinical Molecular Biology, Christian-Albrecht-Universitat, 24105 Kiel, Germany. ; Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. ; Division of Cardiovascular and Neuronal Remodelling, Multidisciplinary Cardiovascular Research Centre, Leeds Institute of Genetics, Health and Therapeutics, University of Leeds, Leeds LS2 9JT, UK. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Charite Research Group on Geriatrics, Charite-Universitatsmedizin, 10117 Berlin, Germany. ; 1] Center for Lifespan Psychology, Max Planck Institute for Human Development, 14195 Berlin, Germany [2] Department of Psychology, TU Dresden, 01062 Dresden, Germany. ; 1] Synlab Academy and Business Development, synlab Services GmbH, 68165 Mannheim, Germany [2] Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, 8036 Graz, Austria [3] Medical Clinic V, Medical Faculty Mannheim, University of Heidelberg, 68167 Mannheim, Germany. ; The Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Cardiovascular Research Center and Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [2] Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02215, USA [3] Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02215, USA. ; University of Ottawa, Heart Institute, Ottawa, Ontario K1Y 4W7, Canada. ; 1] Centrum fur Thrombose und Hamostase (CTH), Universitatsmedizin Mainz, 55131 Mainz, Germany [2] German Centre for Cardiovascular Research (DZHK), partner site RheinMain, 55131 Mainz, Germany. ; 1] Institute of Psychology, Chinese Academy of Sciences, Beijing 100864, China [2] Laboratory of Statistical Genetics, Rockefeller University, New York 10065, USA. ; 1] Deutsches Herzzentrum Munchen and 1. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, 80636 Munchen, Germany [2] Institute of Human Genetics, Helmholtz Zentrum Munchen, German Research Center for Environmental Health, 85764 Neuherberg, Germany [3] Institute of Human Genetics, Technische Universitat Munchen, 81675 Munchen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24213632" target="_blank"〉PubMed〈/a〉