Genetics of Pulmonary Arterial Hypertension

Overview

Journal Semin Respir Crit Care Med

Specialties Critical Care
Pulmonary Medicine

Date 2009 Jul 28

PMID 19634078

Citations 22

Authors

Eric D Austin

James E Loyd

John A Phillips 3rd

Affiliations

Soon will be listed here.

Abstract

Tremendous progress has been made in understanding the genetics of hereditable pulmonary arterial hypertension (HPAH) since its description in the 1950s. Germline mutations in the gene coding bone morphogenetic receptor type 2 ( BMPR2) are detectable in the majority of cases of HPAH, and in a small proportion of cases of idiopathic pulmonary arterial hypertension (IPAH). HPAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, female predominance, and genetic anticipation. These characteristics suggest that endogenous and exogenous factors modify disease expression and areas of emphasis for future investigation. The variable clinical expression makes genetic counseling complex because the majority of carriers of a BMPR2 mutation will not be diagnosed with the disease. This issue will become increasingly important, as clinical testing for BMPR2 mutations is now available for the evaluation of patients and family members with HPAH and IPAH.

Citing Articles

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References

Derynck R, Zhang Y . Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003; 425(6958):577-84. DOI: 10.1038/nature02006. View

Khajavi M, Inoue K, Lupski J . Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet. 2006; 14(10):1074-81. DOI: 10.1038/sj.ejhg.5201649. View

Pearson C, Edamura K, Cleary J . Repeat instability: mechanisms of dynamic mutations. Nat Rev Genet. 2005; 6(10):729-42. DOI: 10.1038/nrg1689. View

Morse J, Jones A, Barst R, Hodge S, Wilhelmsen K, Nygaard T . Mapping of familial primary pulmonary hypertension locus (PPH1) to chromosome 2q31-q32. Circulation. 1997; 95(12):2603-6. DOI: 10.1161/01.cir.95.12.2603. View

Nichols W, Koller D, Slovis B, Foroud T, Terry V, Arnold N . Localization of the gene for familial primary pulmonary hypertension to chromosome 2q31-32. Nat Genet. 1997; 15(3):277-80. DOI: 10.1038/ng0397-277. View

Loyd J, Primm R, Newman J . Familial primary pulmonary hypertension: clinical patterns. Am Rev Respir Dis. 1984; 129(1):194-7. DOI: 10.1164/arrd.1984.129.1.194. View

Koehler R, Olschewski H, Hoeper M, Janssen B, Grunig E . Serotonin transporter gene polymorphism in a cohort of German patients with idiopathic pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Chest. 2005; 128(6 Suppl):619S. DOI: 10.1378/chest.128.6_suppl.619S. View

Chaouat A, Coulet F, Favre C, Simonneau G, Weitzenblum E, Soubrier F . Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax. 2004; 59(5):446-8. PMC: 1746994. DOI: 10.1136/thx.2003.11890. View

Hoeper M, Tacacs A, Stellmacher U, Lichtinghagen R . Lack of association between angiotensin converting enzyme (ACE) genotype, serum ACE activity, and haemodynamics in patients with primary pulmonary hypertension. Heart. 2003; 89(4):445-6. PMC: 1769272. DOI: 10.1136/heart.89.4.445. View

10.

Sztrymf B, Yaici A, Girerd B, Humbert M . Genes and pulmonary arterial hypertension. Respiration. 2007; 74(2):123-32. DOI: 10.1159/000098818. View

11.

Aldred M, Vijayakrishnan J, James V, Soubrier F, Gomez-Sanchez M, Martensson G . BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat. 2006; 27(2):212-3. DOI: 10.1002/humu.9398. View

12.

Lee S, Wang W, Finlay G, Fanburg B . Serotonin stimulates mitogen-activated protein kinase activity through the formation of superoxide anion. Am J Physiol. 1999; 277(2):L282-91. DOI: 10.1152/ajplung.1999.277.2.L282. View

13.

McGoon M, Gutterman D, Steen V, Barst R, McCrory D, Fortin T . Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest. 2004; 126(1 Suppl):14S-34S. DOI: 10.1378/chest.126.1_suppl.14S. View

14.

Sztrymf B, Yaici A, Jais X, Sitbon O, Simonneau G, Humbert M . Idiopathic pulmonary hypertension: what did we learn from genes?. Sarcoidosis Vasc Diffuse Lung Dis. 2006; 22 Suppl 1:S91-100. View

15.

Gaine S, Rubin L . Primary pulmonary hypertension. Lancet. 1998; 352(9129):719-25. DOI: 10.1016/S0140-6736(98)02111-4. View

16.

Machado R, James V, Southwood M, Harrison R, Atkinson C, Stewart S . Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension. Circulation. 2005; 111(5):607-13. DOI: 10.1161/01.CIR.0000154543.07679.08. View

17.

Newman J . Pulmonary hypertension. Am J Respir Crit Care Med. 2005; 172(9):1072-7. PMC: 2718396. DOI: 10.1164/rccm.200505-684OE. View

18.

Newman J, Trembath R, Morse J, Grunig E, Loyd J, Adnot S . Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004; 43(12 Suppl S):33S-39S. DOI: 10.1016/j.jacc.2004.02.028. View

19.

Morrell N . Pulmonary hypertension due to BMPR2 mutation: a new paradigm for tissue remodeling?. Proc Am Thorac Soc. 2006; 3(8):680-6. DOI: 10.1513/pats.200605-118SF. View

20.

Fujiwara M, Yagi H, Matsuoka R, Akimoto K, Furutani M, Imamura S . Implications of mutations of activin receptor-like kinase 1 gene (ALK1) in addition to bone morphogenetic protein receptor II gene (BMPR2) in children with pulmonary arterial hypertension. Circ J. 2007; 72(1):127-33. DOI: 10.1253/circj.72.127. View