The genetics of pulmonary hypertension
Abstract
Recent clinical and experimental studies data are considering relating to the genetic causes of pulmonary arterial hypertension (PAH). The genetic abnormalities were first identified in association with the idiopathic and familial form of PAH, and some cases of secondary PAH following congenital heart defects (CHD). Genetic polymorphism of BMPR2, SMADs, ALK1/ENG were described as a reason of TGF-β-cell signaling disturbances. These genetic abnormalities were found in 6—18,2% of the patients with PAH owing to CHD. There are 70-80% heterozygote carriers of BMPR2-gene mutation among the relatives of familial PAH patients. The effects of the abnormal BMPR2 signaling pathway develop with the participation of ALK-receptors and transcriptional SMAD-proteins. Then BMPR2 и BMPR1B dysfunction culminate in an expressed smooth cells proliferative response that occludes the pulmonary arterial lumen and increases the apoptosis of the endoteliocytes in the small pulmonary arteries.
Keywords
About the Authors
L. V. Bregel
Irkutsk state medical Academy of postgraduate education
Russian Federation
Russian Federation
Yu. M. Belozerov
Research Clinical Institute of Pediatrics; Moscow
Russian Federation
Russian Federation
P. V. Novikov
Research Clinical Institute of Pediatrics; Moscow
Russian Federation
Russian Federation
M. A. Shkolnikova
Research Clinical Institute of Pediatrics; Moscow
Russian Federation
Russian Federation
References
1. Machado R.D., Eickelberg O., Elliott C.G. et al. Genetics and genomics of pulmonary arterial hypertension. J Am Coll Cardiol 2009; 54:1: S32—S42.
2. Pfarr N., Fischer C., Ehlken N. et al. Hemodynamic and genetic analysis in children with idiopathic, heritable, and congenital heart disease associated pulmonary arterial hypertension. Res Res. 2013; 14: 3.
3. Rabinovitch M. Molecular pathogenesis of pulmonary arterial hypertension. J Clin Invest. 2012; 122:12: 4306—4313.
4. Lane K.B., Machado R.D., Pauciulo M.W. et al. Heterozygous germline mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension: The International PPH Consortium. Nat Genet 2000; 26: 81—84.
5. Sankelo M., Flanagan J.A., Machado R. et al. BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension. Hum Mutat 2005; 26: 2: 119—124.
6. Deng Z., Morse J.H., Slager S.L. 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.
7. Harrison R.E., Berger R., Haworth S.G. et al. Transforming growth factor-beta, receptor mutations and pulmonary arterial hypertension in childhood. Circulation 2005; 111: 435— 441.
8. Humbert M., Deng Z., Simonneau G. et al. BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives. Eur Res J 2002; 20: 518—523.
9. Kang H., Davis-Dusenbery B.N., Nguyen P.H. et al. Bone morphogenetic protein 4 promotes vascular smooth muscle contractility by activating microRNA-21 (miR-21), which down-regulates expression of family of dedicator of cytokinesis (DOCK) proteins. J Biol Chem 2012; 287: 6: 3976—3986.
10. Takeda M., Otsuka F., Nakamura K. 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 1B receptor (activin receptor-like kinase 6) in the mitotic action. Endocrinology 2004; 145: 4344—4354.
11. Yu P.B., Beppu H., Kawai N. et al. Bone morphogenetic protein (BMP) type II receptor deletion reveals BMP ligandspecific gain of signaling in pulmonary artery smooth muscle cells. J Biol Chem 2005; 280: 2443—2450.
12. Abdalla S., Letarte M. Hereditary haemorrhagic teleangiectasia: current views on genetics and mechanisms of disease. J Med Genet 2006; 43: 2: 97—110
13. Trembath R.C., Thomson J.R., Machado R.D. et al. Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345: 325—334.
14. Chida A., Shintani M., Nakayama T. et al. Missense mutations of the BMPR1B (ALK6) Gene in Childhood Idiopathic Pulmonary Arterial Hypertension. Circ J 2012; 76: 1501—1508.
15. Roberts K.E., McElroy J.J., Wong W.P. et al. BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease. Eur Respir J 2004; 24: 371—374.
16. Machado R.D., Pauciulo M.W., Thomson J.R. et al. BMPR2 haploinsufficiency as the inherited molecular mechanism for primary pulmonary hypertension. Am J Hum Genet 2001; 68: 92—102.
17. Galie N., Hoeper M.M., Humbert M. et al. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2009; 34: 1219—1263.
18. Simonneau G., Robbins I.M., Beghetti M. et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2009; 54: S43—54.
19. Drake K.M., Zygmunt D., Mavrakis L. et al. Altered MicroRNA processing in heritable pulmonary arterial hypertension: an important role for Smad-8. Am J Res Crit Care Med 2011; 184: 12: 1400—1408.
20. Nasim M.T., Ogo T., Ahmed M. et al. Molecular genetic characterization of SMAD signaling molecules in pulmonary arterial hypertension. Hum Mutat 2011; 32: 12: 1385—1389.
21. Sztrymf B., Coulet F., Girerd B. et al. Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Res Crit Care Med 2008; 177: 1377—1383.
Review
For citations:
Bregel L.V., Belozerov Yu.M., Novikov P.V., Shkolnikova M.A. The genetics of pulmonary hypertension. Rossiyskiy Vestnik Perinatologii i Pediatrii (Russian Bulletin of Perinatology and Pediatrics). 2014;59(1):22-27. (In Russ.)
Views:
809
Email this article 