Correction of nonsense BMPR2 and SMAD9 mutations by ataluren in pulmonary arterial hypertension

American Journal of Respiratory Cell and Molecular Biology

Volumn 49, Issue 3, 2013, Pages 403-409

  Drake, Kylie M ^a   Dunmore, Benjamin J ^c   McNelly, Lauren N ^a   Morrell, Nicholas W ^c   Aldred, Micheala A ^a,b  

^a LERNER RESEARCH INSTITUTE   (United States)

^b TAUSSIG CANCER INSTITUTE   (United States)

^c UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

Ataluren; Bone morphogenetic protein signaling; Nonsense mutation; Pulmonary arterial hypertension

Indexed keywords

ATALUREN; BONE MORPHOGENETIC PROTEIN 2; BONE MORPHOGENETIC PROTEIN RECEPTOR 2; MICRORNA; SMAD PROTEIN; SMAD9 PROTEIN; UNCLASSIFIED DRUG;

ARTICLE; DOSE RESPONSE; DOWNSTREAM PROCESSING; DRUG BIOAVAILABILITY; DRUG MECHANISM; ENDOTHELIUM CELL; HUMAN; HUMAN CELL; IN VITRO STUDY; NONSENSE MUTATION; PHENOTYPE; POINT MUTATION; PROTEIN PHOSPHORYLATION; PULMONARY ARTERY; PULMONARY HYPERTENSION; SIGNAL TRANSDUCTION; SMOOTH MUSCLE FIBER; STOP CODON;

BONE MORPHOGENETIC PROTEIN RECEPTORS, TYPE II; CELL PROLIFERATION; CELLS, CULTURED; CODON, NONSENSE; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUGS, INVESTIGATIONAL; GENE EXPRESSION REGULATION; HETEROZYGOTE; HUMANS; HYPERTENSION, PULMONARY; MICRORNAS; MYOCYTES, SMOOTH MUSCLE; NONSENSE MEDIATED MRNA DECAY; OXADIAZOLES; PULMONARY ARTERY; SIGNAL TRANSDUCTION; SMAD8 PROTEIN;

EID: 84883480295     PISSN: 10441549     EISSN: 15354989     Source Type: Journal    
DOI: 10.1165/rcmb.2013-0100OC     Document Type: Article

References (51)

1. Larkin EK, Newman JH, Austin ED, Hemnes AR, Wheeler L, Robbins IM, West JD, Phillips JA III, Hamid R, Loyd JE. Longitudinal analysis casts doubt on the presence of genetic anticipation in heritable pulmonary arterial hypertension. Am J Respir Crit Care Med 2012;186:892-896.
2. Simonneau G, Robbins IM, Beghetti M, Channick RN, Delcroix M, Denton CP, Elliott CG, Gaine SP, Gladwin MT, Jing ZC, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009;54:S43-S54.
3. 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:S32-S42.
4. 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. (Pubitemid 30659603)
5. 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.
6. Machado RD, Aldred MA, James V, Harrison RE, Patel B, Schwalbe EC, Gruenig E, Janssen B, Koehler R, Seeger W, et al. Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006;27:121-132. (Pubitemid 43238027)
7. Koehler R, Grünig E, Pauciulo MW, Hoeper MM, Olschewski H, Wilkens H, Halank M, Winkler J, Ewert R, Bremer H, et al. Low frequency of BMPR2 mutations in a German cohort of patients with sporadic idiopathic pulmonary arterial hypertension. J Med Genet 2004;41:e127.
8. Morisaki H, Nakanishi N, Kyotani S, Takashima A, Tomoike H, Morisaki T. BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary hypertension. Hum Mutat 2004;23:632.
9. Trembath RC. Mutations in the TGF-beta type 1 receptor, ALK1, in combined primary pulmonary hypertension and hereditary haemorrhagic telangiectasia, implies pathway specificity. J Heart Lung Transplant 2001;20:175.
10. Harrison RE, Flanagan JA, Sankelo M, Abdalla SA, Rowell J, Machado RD, Elliott CG, Robbins IM, Olschewski H, McLaughlin V, et al. Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia. J Med Genet 2003;40:865-871. (Pubitemid 38117534)
11. Abdalla SA, Gallione CJ, Barst RJ, Horn EM, Knowles JA, Marchuk DA, Letarte M, Morse JH. Primary pulmonary hypertension in families with hereditary haemorrhagic telangiectasia. Eur Respir J 2004;23:373-377. (Pubitemid 38344371)
12. Harrison RE, Berger R, Haworth SG, Tulloh R, Mache CJ, Morrell NW, Aldred MA, Trembath RC. Transforming growth factor-beta receptor mutations and pulmonary arterial hypertension in childhood. Circulation 2005;111:435-441. (Pubitemid 40204427)
13. Mache CJ, Gamillscheg A, Popper HH, Haworth SG. Early-life pulmonary arterial hypertension with subsequent development of diffuse pulmonary arteriovenous malformations in hereditary haemorrhagic telangiectasia type 1. Thorax 2008;63:85-86.
14. Shintani M, Yagi H, Nakayama T, Saji T, Matsuoka R. A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension. J Med Genet 2009;46:331-337.
15. Nasim MT, Ogo T, Ahmed M, Randall R, Chowdhury HM, Snape KM, Bradshaw TY, Southgate L, Lee GJ, Jackson I, et al. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 2011;32:1385-1389.
16. 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.
17. Davis BN, Hilyard AC, Lagna G, Hata A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 2008;454:56-61. (Pubitemid 351931982)
18. Davis BN, Hilyard AC, Nguyen PH, Lagna G, Hata A. Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. Mol Cell 2010;39:373-384.
19. Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, et al. Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers. J Clin Pharmacol 2007;47:430-444. (Pubitemid 46465953)
20. Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, Paushkin S, Patel M, Trotta CR, Hwang S, et al. PTC124 targets genetic disorders caused by nonsense mutations. Nature 2007;447:87-91. (Pubitemid 46685839)
21. Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008;372:719-727.
22. Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, et al. Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis. Am J Respir Crit Care Med 2010;182:1262-1272.
23. Wilschanski M, Miller LL, Shoseyov D, Blau H, Rivlin J, Aviram M, Cohen M, Armoni S, Yaakov Y, Pugatsch T, et al. Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis. Eur Respir J 2011;38:59-69.
24. Aytekin M, Comhair SA, de la Motte C, Bandyopadhyay SK, Farver CF, Hascall VC, Erzurum SC, Dweik RA. High levels of hyaluronan in idiopathic pulmonary arterial hypertension. Am J Physiol Lung Cell Mol Physiol 2008;295:L789-L799.
25. Comhair SA, Xu W, Mavrakis L, Aldred MA, Asosingh K, Erzurum SC. Human primary lung endothelial cells in culture. Am J Respir Cell Mol Biol 2012;46:723-730.
26. Toshner M, Voswinckel R, Southwood M, Al-Lamki R, Howard LS, Marchesan D, Yang J, Suntharalingam J, Soon E, Exley A, et al. Evidence of dysfunction of endothelial progenitors in pulmonary arterial hypertension. Am J Respir Crit Care Med 2009;180:780-787.
27. Aldred MA, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez MA, Martensson G, Galie N, Manes A, Corris P, Simonneau G, et al. BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212-213.
28. Asosingh K, Aldred MA, Vasanji A, Drazba J, Sharp J, Farver C, Comhair SA, Xu W, Licina L, Huang L, et al. Circulating angiogenic precursors in idiopathic pulmonary arterial hypertension. Am J Pathol 2008;172:615-627. (Pubitemid 351354535)
29. Upton PD, Davies RJ, Trembath RC, Morrell NW. Bone morphogenetic protein (BMP) and activin type II receptors balance BMP9 signals mediated by activin receptor-like kinase-1 in human pulmonary artery endothelial cells. J Biol Chem 2009;284:15794-15804.
30. Kane GC, Maradit-Kremers H, Slusser JP, Scott CG, Frantz RP, McGoon MD. Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest 2011;139:1285-1293.
31. Benza RL, Miller DP, Barst RJ, Badesch DB, Frost AE, McGoon MD. An evaluation of long-term survival from time of diagnosis in pulmonary arterial hypertension from the REVEAL Registry. Chest 2012;142:448-456.
32. Boutet K, Montani D, Jaïs X, Yaïci A, Sitbon O, Simonneau G, Humbert M. Therapeutic advances in pulmonary arterial hypertension. Ther Adv Respir Dis 2008;2:249-265.
33. Gomberg-Maitland M, Dufton C, Oudiz RJ, Benza RL. Compelling evidence of long-term outcomes in pulmonary arterial hypertension? A clinical perspective. J Am Coll Cardiol 2011;57:1053-1061.
34. Frumkin LR. The pharmacological treatment of pulmonary arterial hypertension. Pharmacol Rev 2012;64:583-620.
35. Elliott CG, Glissmeyer EW, Havlena GT, Carlquist J, McKinney JT, Rich S, McGoon MD, Scholand MB, Kim M, Jensen RL, et al. Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006;113:2509-2515. (Pubitemid 43948029)
36. Sztrymf B, Coulet F, Girerd B, Yaici A, Jais X, Sitbon O, Montani D, Souza R, Simonneau G, Soubrier F, et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008;177:1377-1383. (Pubitemid 351860916)
37. Rosenzweig EB, Morse JH, Knowles JA, Chada KK, Khan AM, Roberts KE, McElroy JJ, Juskiw NK, Mallory NC, Rich S, et al. Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 2008;27:668-674.
38. Reynolds AM, Holmes MD, Danilov SM, Reynolds PN. Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J 2012;39:329-343.
39. Clancy JP, Bebök Z, Ruiz F, King C, Jones J, Walker L, Greer H, Hong J, Wing L, Macaluso M, et al. Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am J Respir Crit Care Med 2001;163:1683-1692. (Pubitemid 32578776)
40. Wilschanski M, Yahav Y, Yaacov Y, Blau H, Bentur L, Rivlin J, Aviram M, Bdolah-Abram T, Bebok Z, Shushi L, et al. Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med 2003;349:1433-1441. (Pubitemid 37211058)
41. Barton-Davis ER, Cordier L, Shoturma DI, Leland SE, Sweeney HL. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest 1999;104:375-381. (Pubitemid 29534321)
42. Wagner KR, Hamed S, Hadley DW, Gropman AL, Burstein AH, Escolar DM, Hoffman EP, Fischbeck KH. Gentamicin treatment of Duchenne and Becker muscular dystrophy due to nonsense mutations. Ann Neurol 2001;49:706-711. (Pubitemid 32530236)
43. Nasim MT, Ghouri A, Patel B, James V, Rudarakanchana N, Morrell NW, Trembath RC. Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension. Hum Mol Genet 2008;17:1683-1694. (Pubitemid 351737172)
44. Hamid R, Hedges LK, Austin E, Phillips JA III, Loyd JE, Cogan JD. Transcripts from a novel BMPR2 termination mutation escape nonsense mediated decay by downstream translation re-initiation: implications for treating pulmonary hypertension. Clin Genet 2010;77:280-286.
45. Lopez-Novoa JM, Quiros Y, Vicente L, Morales AI, Lopez-Hernandez FJ. New insights into the mechanism of aminoglycoside nephrotoxicity: an integrative point of view. Kidney Int 2011;79:33-45.
46. Warchol ME. Cellular mechanisms of aminoglycoside ototoxicity. Curr Opin Otolaryngol Head Neck Surg 2010;18:454-458.
47. Linde L, Boelz S, Nissim-Rafinia M, Oren YS, Wilschanski M, Yaacov Y, Virgilis D, Neu-Yilik G, Kulozik AE, Kerem E, et al. Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest 2007;117:683-692. (Pubitemid 46348526)
48. Durrington HJ, Upton PD, Hoer S, Boname J, Dunmore BJ, Yang J, Crilley TK, Butler LM, Blackbourn DJ, Nash GB, et al. Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II. J Biol Chem 2010;285:37641-37649.
49. Li W, Dunmore BJ, Morrell NW. Bone morphogenetic protein type II receptor mutations causing protein misfolding in heritable pulmonary arterial hypertension. Proc Am Thorac Soc 2010;7:395-398.
50. Sobolewski A, Rudarakanchana N, Upton PD, Yang J, Crilley TK, Trembath RC, Morrell NW. Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue. Hum Mol Genet 2008;17:3180-3190.
51. Girerd B, Montani D, Coulet F, Sztrymf B, Yaici A, Jaïs X, Tregouet D, Reis A, Drouin-Garraud V, Fraisse A, et al. Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010;181:851-861.