Novel thrombotic function of a human SNP in STXBP5 revealed by CRISPR/Cas9 gene editing in mice

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 37, Issue 2, 2017, Pages 264-270

  Zhu, Qiuyu Martin ^a   Ko, Kyung Ae ^a   Ture, Sara ^a   Mastrangelo, Michael A ^a   Chen, Ming Huei ^b   Johnson, Andrew D ^b   O'Donnell, Christopher J ^b,c   Morrell, Craig N ^a   Miano, Joseph M ^a   Lowenstein, Charles J ^a  

^a UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

^b FRAMINGHAM HEART STUDY   (United States)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

Author keywords

gene editing; genome wide association study; phenotype; thrombosis; von Willebrand factor

Indexed keywords

BINDING PROTEIN; GENOMIC DNA; REGULATOR PROTEIN; SYNTAXIN; SYNTAXIN BINDING PROTEIN 5; THROMBIN; THROMBOCYTE FACTOR 4; UNCLASSIFIED DRUG; VON WILLEBRAND FACTOR; CRISPR ASSOCIATED PROTEIN; NERVE PROTEIN; STXBP5 PROTEIN, HUMAN; SYNAPTOBREVIN;

ALLELE; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; COMPARATIVE STUDY; CONTROLLED STUDY; CRISPR CAS SYSTEM; CRISPR CAS9 SYSTEM; EXOCYTOSIS; GENE EDITING; GENE MUTATION; GENETIC ASSOCIATION; GENETIC VARIABILITY; GENETIC VARIATION; IN VIVO STUDY; MOLECULAR PATHOLOGY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; QUANTITATIVE TRAIT LOCUS; SINGLE NUCLEOTIDE POLYMORPHISM; THROMBOCYTE ACTIVATION; THROMBOCYTE RELEASE REACTION; THROMBOSIS; ANIMAL; BLOOD; BLOOD CLOTTING; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEAT; DISEASE MODEL; DOWN REGULATION; GENETICS; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HUMAN; METABOLISM; PHENOTYPE; PROCEDURES; THROMBOCYTE; TRANSGENIC MOUSE;

ANIMALS; BLOOD COAGULATION; BLOOD PLATELETS; CLUSTERED REGULARLY INTERSPACED SHORT PALINDROMIC REPEATS; CRISPR-ASSOCIATED PROTEINS; CRISPR-CAS SYSTEMS; DISEASE MODELS, ANIMAL; DOWN-REGULATION; EXOCYTOSIS; GENE EDITING; GENOME-WIDE ASSOCIATION STUDY; GENOTYPE; HUMANS; MICE, TRANSGENIC; NERVE TISSUE PROTEINS; PHENOTYPE; PLATELET ACTIVATION; POLYMORPHISM, SINGLE NUCLEOTIDE; R-SNARE PROTEINS; THROMBOSIS; VON WILLEBRAND FACTOR;

EID: 85011114106     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.116.308614     Document Type: Article

References (37)

1. Spiel AO, Gilbert JC, Jilma B. von Willebrand factor in cardiovascular disease: focus on acute coronary syndromes. Circulation. 2008;117:1449-1459. doi: 10.1161/CIRCULATIONAHA.107.722827.
2. Smith NL, Chen MH, Dehghan A, et al; Wellcome Trust Case Control Consortium. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation. 2010;121:1382-1392. doi: 10.1161/ CIRCULATIONAHA.109.869156.
3. Antoni G, Oudot-Mellakh T, Dimitromanolakis A, Germain M, Cohen W, Wells P, Lathrop M, Gagnon F, Morange PE, Tregouet DA. Combined analysis of three genome-wide association studies on vWF and FVIII plasma levels. BMC Med Genet. 2011;12:102. doi: 10.1186/1471-2350-12-102.
4. van Loon JE, Leebeek FW, Deckers JW, Dippel DW, Poldermans D, Strachan DP, Tang W, O'Donnell CJ, Smith NL, de Maat MP. Effect of genetic variations in syntaxin-binding protein-5 and syntaxin-2 on von Willebrand factor concentration and cardiovascular risk. Circ Cardiovasc Genet. 2010;3:507-512. doi: 10.1161/CIRCGENETICS. 110.957407.
5. Sanders YV, van der Bom JG, Isaacs A, Cnossen MH, de Maat MP, Larosvan Gorkom BA, Fijnvandraat K, Meijer K, van Duijn CM, Mauser-Bunschoten EP, Eikenboom J, Leebeek FW; WiN Study Group. CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease. J Thromb Haemost. 2015;13:956-966. doi: 10.1111/jth.12927.
6. van Loon J, Dehghan A, Weihong T, et al. Genome-wide association studies identify genetic loci for low von Willebrand factor levels. Eur J Hum Genet. 2016;24:1035-1040. doi: 10.1038/ejhg.2015.222.
7. Rydz N, Swystun LL, Notley C, Paterson AD, Riches JJ, Sponagle K, Boonyawat B, Montgomery RR, James PD, Lillicrap D. The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels. Blood. 2013;121:5228-5237. doi: 10.1182/blood-2012-10-457507.
8. van Loon JE, Sanders YV, de Wee EM, Kruip MJ, de Maat MP, Leebeek FW. Effect of genetic variation in STXBP5 and STX2 on von Willebrand factor and bleeding phenotype in type 1 von Willebrand disease patients. PLoS One. 2012;7:e40624. doi: 10.1371/journal. pone.0040624.
9. Smith NL, Rice KM, Bovill EG, et al. Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis. Blood. 2011;117:6007-6011. doi: 10.1182/ blood-2010-10-315473.
10. Zhu Q, Yamakuchi M, Ture S, de la Luz Garcia-Hernandez M, Ko KA, Modjeski KL, LoMonaco MB, Johnson AD, O'Donnell CJ, Takai Y, Morrell CN, Lowenstein CJ. Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion. J Clin Invest. 2014;124:4503-4516. doi: 10.1172/JCI71245.
11. Ye S, Huang Y, Joshi S, Zhang J, Yang F, Zhang G, Smyth SS, Li Z, Takai Y, Whiteheart SW. Platelet secretion and hemostasis require syntaxin-binding protein STXBP5. J Clin Invest. 2014;124:4517-4528. doi: 10.1172/JCI75572.
12. Lillicrap D. Syntaxin-binding protein 5 exocytosis regulation: differential role in endothelial cells and platelets. J Clin Invest. 2014;124:4231-4233. doi: 10.1172/JCI77511.
13. Gupta RM, Musunuru K. Expanding the genetic editing tool kit: ZFNs, TALENs, and CRISPR-Cas9. J Clin Invest. 2014;124:4154-4161. doi: 10.1172/JCI72992.
14. Hsu PD, Lander ES, Zhang F. Development and applications of CRISPRCas9 for genome engineering. Cell. 2014;157:1262-1278. doi: 10.1016/j. cell.2014.05.010.
15. Miano JM, Zhu QM, Lowenstein CJ. A CRISPR path to engineering new genetic mouse models for cardiovascular research. Arterioscler Thromb Vasc Biol. 2016;36:1058-1075. doi: 10.1161/ ATVBAHA.116.304790.
16. Yang H, Wang H, Jaenisch R. Generating genetically modified mice using CRISPR/Cas-mediated genome engineering. Nat Protoc. 2014;9:1956-1968. doi: 10.1038/nprot.2014.134.
17. Wang H, Yang H, Shivalila CS, Dawlaty MM, Cheng AW, Zhang F, Jaenisch R. One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering. Cell. 2013;153:910-918. doi: 10.1016/j.cell.2013.04.025.
18. Han Y, Slivano OJ, Christie CK, Cheng AW, Miano JM. CRISPR-Cas9 genome editing of a single regulatory element nearly abolishes target gene expression in mice-brief report. Arterioscler Thromb Vasc Biol. 2015;35:312-315. doi: 10.1161/ATVBAHA.114.305017.
19. Sauna ZE, Kimchi-Sarfaty C. Understanding the contribution of synonymous mutations to human disease. Nat Rev Genet. 2011;12:683-691. doi: 10.1038/nrg3051.
20. Consortium EP. An integrated Encyclopedia of DNA Elements in the human genome. Nature. 2012;489:57-74.
21. Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(database issue):D930-D934. doi: 10.1093/nar/gkr917.
22. Visel A, Rubin EM, Pennacchio LA. Genomic views of distant-acting enhancers. Nature. 2009;461:199-205. doi: 10.1038/nature08451.
23. Rao SS, Huntley MH, Durand NC, Stamenova EK, Bochkov ID, Robinson JT, Sanborn AL, Machol I, Omer AD, Lander ES, Aiden EL. A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping. Cell. 2014;159:1665-1680. doi: 10.1016/j. cell.2014.11.021.
24. Lieberman-Aiden E, van Berkum NL, Williams L, et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science. 2009;326:289-293. doi: 10.1126/science.1181369.
25. Fullwood MJ, Liu MH, Pan YF, et al. An oestrogen-receptor-alpha-bound human chromatin interactome. Nature. 2009;462:58-64. doi: 10.1038/ nature08497.
26. Consortium GT. Human genomics. The genotype-tissue expression (gtex) pilot analysis: multitissue gene regulation in humans. Science. 2015;348:648-660.
27. Arnold M, Raffler J, Pfeufer A, Suhre K, Kastenmüller G. SNiPA: an interactive, genetic variant-centered annotation browser. Bioinformatics. 2015;31:1334-1336. doi: 10.1093/bioinformatics/btu779.
28. Pobbati AV, Razeto A, Böddener M, Becker S, Fasshauer D. Structural basis for the inhibitory role of tomosyn in exocytosis. J Biol Chem. 2004;279:47192-47200. doi: 10.1074/jbc.M408767200.
29. Baba T, Sakisaka T, Mochida S, Takai Y. PKA-catalyzed phosphorylation of tomosyn and its implication in Ca2+-dependent exocytosis of neurotransmitter. J Cell Biol. 2005;170:1113-1125. doi: 10.1083/ jcb.200504055.
30. Yizhar O, Lipstein N, Gladycheva SE, Matti U, Ernst SA, Rettig J, Stuenkel EL, Ashery U. Multiple functional domains are involved in tomosyn regulation of exocytosis. J Neurochem. 2007;103:604-616. doi: 10.1111/j.1471-4159.2007.04791.x.
31. Sakisaka T, Yamamoto Y, Mochida S, Nakamura M, Nishikawa K, Ishizaki H, Okamoto-Tanaka M, Miyoshi J, Fujiyoshi Y, Manabe T, Takai Y. Dual inhibition of SNARE complex formation by tomosyn ensures controlled neurotransmitter release. J Cell Biol. 2008;183:323-337. doi: 10.1083/ jcb.200805150.
32. Yamamoto Y, Mochida S, Miyazaki N, Kawai K, Fujikura K, Kurooka T, Iwasaki K, Sakisaka T. Tomosyn inhibits synaptotagmin-1-mediated step of Ca2+-dependent neurotransmitter release through its N-terminal WD40 repeats. J Biol Chem. 2010;285:40943-40955. doi: 10.1074/jbc. M110.156893.
33. Williams AL, Bielopolski N, Meroz D, Lam AD, Passmore DR, Ben-Tal N, Ernst SA, Ashery U, Stuenkel EL. Structural and functional analysis of tomosyn identifies domains important in exocytotic regulation. J Biol Chem. 2011;286:14542-14553. doi: 10.1074/jbc.M110.215624.
34. Bielopolski N, Lam AD, Bar-On D, Sauer M, Stuenkel EL, Ashery U. Differential interaction of tomosyn with syntaxin and SNAP25 depends on domains in the WD40 β-propeller core and determines its inhibitory activity. J Biol Chem. 2014;289:17087-17099. doi: 10.1074/jbc. M113.515296.
35. Yu H, Rathore SS, Gulbranson DR, Shen J. The N-and C-terminal domains of tomosyn play distinct roles in soluble N-ethylmaleimidesensitive factor attachment protein receptor binding and fusion regulation. J Biol Chem. 2014;289:25571-25580. doi: 10.1074/jbc.M114.591487.
36. Tsai SQ, Zheng Z, Nguyen NT, Liebers M, Topkar VV, Thapar V, Wyvekens N, Khayter C, Iafrate AJ, Le LP, Aryee MJ, Joung JK. GUIDEseq enables genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol. 2015;33:187-197. doi: 10.1038/nbt.3117.
37. Zhang XH, Tee LY, Wang XG, Huang QS, Yang SH. Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol Ther Nucleic Acids. 2015;4:e264. doi: 10.1038/mtna.2015.37.