Whole-exome sequencing reveals TopBP1 as a novel gene in idiopathic pulmonary arterial hypertension

American Journal of Respiratory and Critical Care Medicine

Volumn 189, Issue 10, 2014, Pages 1260-1272

  De Jesus Perez, Vinicio A ^a   Yuan, Ke ^a   Lyuksyutova, Maria A ^b   Dewey, Frederick ^a,c   Orcholski, Mark E ^a   Shuffle, Eric M ^a   Mathur, Maya ^a,c   Yancy Jr , Luke ^c   Rojas, Vanessa ^a   Li, Caiyun Grace ^a,c   Cao, Aiqin ^a,c   Alastalo, Tero Pekka ^d   Khazeni, Nayer ^a,c   Cimprich, Karlene A ^c   Butte, Atul J ^a,c   Ashley, Euan ^a,c   Zamanian, Roham T ^a  

^a STANFORD UNIVERSITY MEDICAL CENTER   (United States)

^b TEXAS A AND M UNIVERSITY   (United States)

^c STANFORD UNIVERSITY   (United States)

^d UNIVERSITY OF HELSINKI   (Finland)

Author keywords

Bioinformatics; DNA injury; Highthroughput nucleotide sequencing; Pulmonary hypertension; Vascular biology

Indexed keywords

BONE MORPHOGENETIC PROTEIN RECEPTOR 2; CALCIUM CHANNEL BLOCKING AGENT; DNA BINDING PROTEIN; ENDOTHELIN RECEPTOR ANTAGONIST; GENOMIC DNA; HYDROXYUREA; PHOSPHODIESTERASE INHIBITOR; SMALL INTERFERING RNA; TOPOISOMERASE DNA BINDING II BINDING PROTEIN 1; UNCLASSIFIED DRUG;

ADULT; APOPTOSIS; ARTICLE; CELL SURVIVAL; CHROMOSOME; CLINICAL ARTICLE; CONTROLLED STUDY; DNA DAMAGE; DNA REPLICATION; ENDOTHELIUM CELL; EXOME; FEMALE; GENE FREQUENCY; GENE LOCATION; GENE SEQUENCE; GENETIC PROCEDURES; GENETIC RISK; GENETIC SUSCEPTIBILITY; GENETIC VARIABILITY; HEART CATHETERIZATION; HEART OUTPUT; HEART RIGHT ATRIUM PRESSURE; HUMAN; HUMAN CELL; LUNG VASCULAR RESISTANCE; MALE; MICROVASCULAR ENDOTHELIAL CELL; PENETRANCE; PRIORITY JOURNAL; PULMONARY ARTERY OCCLUSION PRESSURE; PULMONARY HYPERTENSION; SINGLE NUCLEOTIDE POLYMORPHISM; VASCULAR LESION; WHOLE EXOME SEQUENCING;

ADULT; BIOLOGICAL MARKERS; CARRIER PROTEINS; DISEASE PROGRESSION; DNA-BINDING PROTEINS; EXOME; FEMALE; GENETIC TESTING; HUMANS; HYPERTENSION, PULMONARY; MALE; MIDDLE AGED; MUTATION; NUCLEAR PROTEINS; PREDICTIVE VALUE OF TESTS; SENSITIVITY AND SPECIFICITY; SEQUENCE ANALYSIS, DNA;

EID: 84901047991     PISSN: 1073449X     EISSN: 15354970     Source Type: Journal    
DOI: 10.1164/rccm.201310-1749OC     Document Type: Article

References (71)

1. McLaughlin V, Humbert M, Coghlan G, Nash P, Steen V. Pulmonary arterial hypertension: the most devastating vascular complication of systemic sclerosis. Rheumatology (Oxford) 2009;48:iii25-iii31.
2. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, et al.; American College of Cardiology Foundation Task Force on Expert Consensus Documents; American Heart Association; American College of Chest Physicians; American Thoracic Society, Inc; Pulmonary Hypertension Association. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol 2009;53:1573-1619.
3. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Ya?ici A, Weitzenblum E, Cordier JF, Chabot F, et al. Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation 2010;122: 156-163.
4. McLaughlin VV, Archer SL, Badesch DB, Barst RJ, Farber HW, Lindner JR, Mathier MA, McGoon MD, Park MH, Rosenson RS, et al.; ACCF/AHA. ACCF/AHA 2009 expert consensus document on pulmonary hypertension: a report of the AmericanCollege of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association: developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association. Circulation 2009;119:2250-2294.
5. Rich S, Dantzker DR, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Koerner SK, et al. Primary pulmonary hypertension. A national prospective study. Ann Intern Med 1987;107:216-223.
6. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest 2008;118:2372-2379.
7. Morrell NW. Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling? Proc Am Thorac Soc 2006;3:680-686.
8. Deng Z, Morse JH, Slager SL, Cuervo N, Moore KJ, Venetos G, Kalachikov S, Cayanis E, Fischer SG, Barst RJ, et al. Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000;67:737-744.
9. Lane KB, Machado RD, Pauciulo MW, Thomson JR, Phillips JA III, Loyd JE, Nichols WC, Trembath RC; International PPH Consortium. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000;26:81-84.
10. Machado RD, Eickelberg O, Elliott CG, Geraci MW, Hanaoka M, Loyd JE, Newman JH, Phillips JA III, Soubrier F, Trembath RC, et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009;54(1 Suppl)S32-S42.
11. Fessel JP, Loyd JE, Austin ED. The genetics of pulmonary arterial hypertension in the post-BMPR2 era. Pulm Circ 2011;1:305-319.
12. Loyd JE. Pulmonary arterial hypertension: insights from genetic studies. Proc Am Thorac Soc 2011;8:154-157.
13. Ku CS, Naidoo N, Pawitan Y. Revisiting Mendelian disorders through exome sequencing. Hum Genet 2011;129:351-370.
14. Piluso G, Aurino S, Cacciottolo M, Del Vecchio Blanco F, Lancioni A, Rotundo IL, Torella A, Nigro V. Mendelian bases of myopathies, cardiomyopathies, and neuromyopathies. Acta Myol 2010;29:1-20.
15. Dewey FE, Chen R, Cordero SP, Ormond KE, Caleshu C, Karczewski KJ, Whirl-Carrillo M, Wheeler MT, Dudley JT, Byrnes JK, et al. Phased whole-genome genetic risk in a family quartet using a major allele reference sequence. PLoS Genet 2011;7:e1002280.
16. Ma L, Roman-Campos D, Austin ED, Eyries M, Sampson KS, Soubrier F, Germain M, Trégouet DA, Borczuk A, Rosenzweig EB, et al. A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013;369:351-361.
17. Austin ED, Ma L, LeDuc C, Berman Rosenzweig E, Borczuk A, Phillips JAIII III, Palomero T, Sumazin P, Kim HR, Talati MH, et al. Whole exome sequencing to identify a novel gene (caveolin-1) associated with human pulmonary arterial hypertension. Circ Cardiovasc Genet 2012;5:336-343.
18. de Jesus Perez V, Lyuksyutova M, Dewey F, del Rosario P, Ashley E, Zamnaian RT. Whole exome sequencing identifies novel candidate genes in a cohort of patients with idiopathic pulmonary arterial hypertension [abstract]. Am J Respir Crit Care Med 2013;187: A2544.
19. Chang X, Wang K. wANNOVAR: annotating genetic variants for personal genomes via the web. J Med Genet 2012;49:433-436.
20. Li MX, Kwan JS, Bao SY, Yang W, Ho SL, Song YQ, Sham PC. Predicting mendelian disease-causing non-synonymous single nucleotide variants in exome sequencing studies. PLoS Genet 2013; 9:e1003143.
21. Liu X, Jian X, Boerwinkle E. dbNSFP v2.0: a database of human nonsynonymous SNVs and their functional predictions and annotations. Hum Mutat 2013;34:E2393-E2402.
22. Chun S, Fay JC. Identification of deleterious mutations within three human genomes. Genome Res 2009;19:1553-1561.
23. Panoutsopoulou K, Tachmazidou I, Zeggini E. In search of lowfrequency and rare variants affecting complex traits. Hum Mol Genet 2013;22:R16-R21.
24. Li MX, Gui HS, Kwan JS, Bao SY, Sham PC. A comprehensive framework for prioritizing variants in exome sequencing studies of Mendelian diseases. Nucleic Acids Res 2012;40:e53.
25. Safran M, Dalah I, Alexander J, Rosen N, Iny Stein T, Shmoish M, Nativ N, Bahir I, Doniger T, Krug H, et al. GeneCards Version 3: the human gene integrator. Database 2010;2010:1-16.
26. Ehrenforth S, Aygören-Pürsün E, Hach-Wunderle V, Scharrer I. Prevalence of elevated histidine-rich glycoprotein in patients with thrombophilia-a study of 695 patients. Thromb Haemost 1994;71: 160-161.
27. Wakabayashi S. New insights into the functions of histidine-rich glycoprotein. Int Rev Cell Mol Biol 2013;304:467-493.
28. Lee C, Dixelius J, Thulin A, Kawamura H, Claesson-Welsh L, Olsson AK. Signal transduction in endothelial cells by the angiogenesis inhibitor histidine-rich glycoprotein targets focal adhesions. Exp Cell Res 2006;312:2547-2556.
29. Poon IK, Parish CR, Hulett MD. Histidine-rich glycoprotein functions cooperatively with cell surface heparan sulfate on phagocytes to promote necrotic cell uptake. J Leukoc Biol 2010;88:559-569.
30. Ohta T, Ikemoto Y, Usami A, Koide T, Wakabayashi S. High affinity interaction between histidine-rich glycoprotein and the cell surface type ATP synthase on T-cells. Biochim Biophys Acta 2009;1788: 1099-1107.
31. Kern CB, Norris RA, Thompson RP, Argraves WS, Fairey SE, Reyes L, Hoffman S, Markwald RR, Mjaatvedt CH. Versican proteolysis mediates myocardial regression during outflow tract development. Dev Dyn 2007;236:671-683.
32. Llorente-Cortés V, Otero-Viñas M, Hurt-Camejo E, Mart́inez-González J, Badimon L. Human coronary smooth muscle cells internalize versican-modified LDL through LDL receptor-related protein and LDL receptors. Arterioscler Thromb Vasc Biol 2002;22:387-393.
33. Wight TN, Merrilees MJ. Proteoglycans in atherosclerosis and restenosis: key roles for versican. Circ Res 2004;94:1158-1167.
34. Didangelos A, Mayr U, Monaco C, Mayr M. Novel role of ADAMTS-5 protein in proteoglycan turnover and lipoprotein retention in atherosclerosis. J Biol Chem 2012;287:19341-19345.
35. Nam EA, Cortez D. ATR signalling: more than meeting at the fork. Biochem J 2011;436:527-536.
36. Kumagai A, Shevchenko A, Shevchenko A, Dunphy WG. Treslin collaborates with TopBP1 in triggering the initiation of DNA replication. Cell 2010;140:349-359.
37. Kumagai A, Lee J, Yoo HY, Dunphy WG. TopBP1 activates the ATRATRIP complex. Cell 2006;124:943-955.
38. Blaut MA, Bogdanova NV, Bremer M, Karstens JH, Hillemanns P, Dörk T. TOPBP1 missense variant Arg309Cys and breast cancer in a German hospital-based case-control study. J Negat Results Biomed 2010;9:9.
39. Germann SM, Oestergaard VH, Haas C, Salis P, Motegi A, Lisby M. Dpb11/TopBP1 plays distinct roles in DNA replication, checkpoint response and homologous recombination. DNA Repair (Amst) 2011;10:210-224.
40. Li M, Vattulainen S, Aho J, Orcholski M, Rojas V, Yuan K, Helenius M, Taimen P, Myllykangas S, De Jesus Perez V, et al. Loss-of BMPR2 is associated with abnormal DNA repair in pulmonary arterial hypertension. Am J Respir Cell Mol Biol (In press)
41. Meloche J, Pflieger A, Vaillancourt M, Paulin R, Potus F, Zervopoulos S, Graydon C, Courboulin A, Breuils-Bonnet S, Tremblay E, et al. Role for DNA damage signaling in pulmonary arterial hypertension. Circulation 2014;129:786-797.
42. Liu K, Lin FT, Ruppert JM, Lin WC. Regulation of E2F1 by BRCT domain-containing protein TopBP1. Mol Cell Biol 2003;23: 3287-3304.
43. Yu L, Hales CA. Silencing of sodium-hydrogen exchanger 1 attenuates the proliferation, hypertrophy, and migration of pulmonary artery smooth muscle cells via E2F1. Am J Respir Cell Mol Biol 2011;45: 923-930.
44. Yang Y, Sun F, Zhang C, Wang H, Wu G, Wu Z. Hypoxia promotes cell proliferation by modulating E2F1 in chicken pulmonary arterial smooth muscle cells. J Animal Sci Biotech 2013;4:28.
45. Edgar RC. MUSCLE: a multiple sequence alignment method with reduced time and space complexity. BMC Bioinformatics 2004;5: 113.
46. Aldred MA, Comhair SA, Varella-Garcia M, Asosingh K, Xu W, Noon GP, Thistlethwaite PA, Tuder RM, Erzurum SC, Geraci MW, et al. Somatic chromosome abnormalities in the lungs of patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2010; 182:1153-1160.
47. Machado RD, James V, Southwood M, Harrison RE, Atkinson C, Stewart S, Morrell NW, Trembath RC, Aldred MA. Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation 2005;111:607-613.
48. Drake KM, Zygmunt D, Mavrakis L, Harbor P, Wang L, Comhair SA, Erzurum SC, Aldred MA. Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Respir Crit Care Med 2011;184:1400-1408.
49. Kovacic P. Hydroxyurea (therapeutics and mechanism): metabolism, carbamoyl nitroso, nitroxyl, radicals, cell signaling and clinical applications. Med Hypotheses 2011;76:24-31.
50. Huh JE, Lee EO, Kim MS, Kang KS, Kim CH, Cha BC, Surh YJ, Kim SH. Penta-O-galloyl-beta-D-glucose suppresses tumor growth via inhibition of angiogenesis and stimulation of apoptosis: roles of cyclooxygenase-2 and mitogen-activated protein kinase pathways. Carcinogenesis 2005;26:1436-1445.
51. Redon C, Pilch D, Rogakou E, Sedelnikova O, Newrock K, Bonner W. Histone H2A variants H2AX and H2AZ. Curr Opin Genet Dev 2002; 12:162-169.
52. Tuder RM, Cool CD, Yeager M, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary hypertension. Endothelium. Clin Chest Med 2001;22:405-418.
53. Spiekerkoetter E, Tian X, Cai J, Hopper RK, Sudheendra D, Li CG, El-Bizri N, Sawada H, Haghighat R, Chan R, et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J Clin Invest 2013;123:3600-3613.
54. Tamosiuniene R, Tian W, Dhillon G, Wang L, Sung YK, Gera L, Patterson AJ, Agrawal R, Rabinovitch M, Ambler K, et al. Regulatory T cells limit vascular endothelial injury and prevent pulmonary hypertension. Circ Res 2011;109:867-879.
55. de Jesus Perez VA, Yuan K, Orcholski ME, Sawada H, Zhao M, Li CG, Tojais NF, Nickel N, Rajagopalan V, Spiekerkoetter E, et al. Loss of adenomatous poliposis coli-a3 integrin interaction promotes endothelial apoptosis in mice and humans. Circ Res 2012;111: 1551-1564.
56. de Jesus Perez VA, Alastalo TP, Wu JC, Axelrod JD, Cooke JP, Amieva M, Rabinovitch M. Bone morphogenetic protein 2 induces pulmonary angiogenesis via Wnt-beta-catenin and Wnt-RhoA-Rac1 pathways. J Cell Biol 2009;184:83-99.
57. Masri FA, Xu W, Comhair SA, Asosingh K, Koo M, Vasanji A, Drazba J, Anand-Apte B, Erzurum SC. Hyperproliferative apoptosis-resistant endothelial cells in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2007;293:L548-L554.
58. Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA, Shendure J. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011;12:745-755.
59. Bartek J, Mailand N. TOPping up ATR activity. Cell 2006;124: 888-890.
60. Cescutti R, Negrini S, Kohzaki M, Halazonetis TD. TopBP1 functions with 53BP1 in the G1 DNA damage checkpoint. EMBO J 2010;29: 3723-3732.
61. Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, Doerks T, Stark M, Muller J, Bork P, et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 2011;39:D561-D568.
62. Souza TA, Chen X, Guo Y, Sava P, Zhang J, Hill JJ, Yaworsky PJ, Qiu Y. Proteomic identification and functional validation of activins and bone morphogenetic protein 11 as candidate novel muscle mass regulators. Mol Endocrinol 2008;22: 2689-2702.
63. Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest 1998;114(3 Suppl):225S-230S.
64. Lee SD, Shroyer KR, Markham NE, Cool CD, Voelkel NF, Tuder RM. Monoclonal endothelial cell proliferation is present in primary but not secondary pulmonary hypertension. J Clin Invest 1998;101:927-934.
65. Rai PR, Cool CD, King JA, Stevens T, Burns N, Winn RA, Kasper M, Voelkel NF. The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;178:558-564.
66. Germain M, Eyries M, Montani D, Poirier O, Girerd B, Dorfmüller P, Coulet F, Nadaud S, Maugenre S, Guignabert C, et al. Genome-wide association analysis identifies a susceptibility locus for pulmonary arterial hypertension. Nat Genet 2013;45:518-521.
67. Majewski J, Schwartzentruber J, Lalonde E, Montpetit A, Jabado N. What can exome sequencing do for you?J Med Genet 2011;48: 580-589.
68. Riancho JA. Genome-wide association studies (GWAS) in complex diseases: advantages and limitations. Reumatol Clin 2012;8:56-57.
69. Dorn GW, Cresci S. Genome-wide association studies of coronary artery disease and heart failure: where are we going? Pharmacogenomics 2009;10:213-223.
70. Takeda M, Otsuka F, Nakamura K, Inagaki K, Suzuki J, Miura D, Fujio H, Matsubara H, Date H, Ohe T, et al. Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action. Endocrinology 2004;145: 4344-4354.
71. El-Bizri N, Wang L, Merklinger SL, Guignabert C, Desai T, Urashima T, Sheikh AY, Knutsen RH, Mecham RP, Mishina Y, et al. Smooth muscle protein 22alpha-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling. Circ Res 2008;102:380-388.