ABSTRACT
Idiopathic pulmonary arterial hypertension (formerly primary pulmonary hypertension)
can affect more than one member of the same family. In the past 25 years scientists
have exposed the inheritance pattern and a major element of the molecular basis for
inherited pulmonary arterial hypertension. Familial pulmonary arterial hypertension
is inherited as an autosomal dominant trait with incomplete penetrance (i.e., several
individuals inherit a predisposition to the disease, but never express it). Mutations
in the gene that codes for bone morphogenetic protein receptor type II (BMPR-II) are
a major predisposition for the development of pulmonary arterial hypertension. These
mutations are present in at least half of familial cases of pulmonary arterial hypertension
and 10 to 25% of idiopathic pulmonary arterial hypertension patients. Mutations in
the gene that codes for activin receptor-like kinase (ALK 1), another transforming
growth factor beta (TGF-β) cell surface receptor, appear responsible for the rare
occurrence of pulmonary arterial hypertension in patients with hereditary hemorrhagic
telangiectasia. These discoveries coupled with other basic investigations offer opportunities
for advances in the management of pulmonary arterial hypertension.
KEYWORDS
Idiopathic pulmonary arterial hypertension - genetics - familial pulmonary arterial
hypertension - primary pulmonary hypertension - pulmonary hypertension
REFERENCES
- 1
Dresdale D T, Michtom R J, Schultaz M.
Recent studies in primary pulmonary hypertension.
Bull N Y Aca Med.
1954;
30
195-207
- 2
Schaffner F.
Clinico-pathological conference.
J Mt Sinai Hosp P Med.
1958;
25
479-494
- 3
Husson G S, Wyatt T C.
Primary pulmonary obliterative vascular disease in infants and young children.
Pediatrics.
1959;
23
493-506
- 4
Sleeper J C, Orgain E S, McIntosh H D.
Primary pulmonary hypertension: review of clinical features and report of pulmonary
hemodynamics derived from repeated catheterization.
Circulation.
1962;
26
1358-1369
- 5
Boiteau G M, Libanoff A J.
Primary pulmonary hypertension: familial incidence.
Angiology.
1963;
14
260-264
- 6
Melmon K L, Braunwald E.
Familial pulmonary hypertension.
N Engl J Med.
1963;
269
770-775
- 7
Rogge J D, Mishkin M E, Genovese P D.
The familial occurrence of primary pulmonary hypertension.
Ann Intern Med.
1966;
65
672-684
- 8
Kingdon H S, Cohen L S, Roberts W C, Braunwald E.
Familial occurrence of primary pulmonary hypertension.
Arch Intern Med.
1966;
118
422-426
- 9
Porter C M, Creech B J, Billings F T.
Primary pulmonary hypertension occurring in twins.
Arch Intern Med.
1967;
120
224-229
- 10
Czarnecki S W, Rosenbaum H M, Wachtel H L.
The occurrence of primary pulmonary hypertension in twins with a review of etiological
considerations.
Am Heart J.
1968;
75
240-246
- 11
Tsagaris T J, Tikoff G.
Familial primary pulmonary hypertension.
Am Rev Respir Dis.
1968;
97
127-130
- 12
Massoud H, Puckett W, Auerbach S H.
Primary pulmonary hypertension: a study of the disease in four young siblings.
J Tenn Med Assoc.
1970;
63
299-305
- 13
Inglesby T V, Singer J W, Gordon D S.
Abnormal fibrinolysis in familial pulmonary hypertension.
Am J Med.
1973;
55
5-14
- 14
Hendrix G H.
Familial primary pulmonary hypertension.
South Med J.
1974;
67
981-983
- 15
Tubbs R R, Levin R D, Sirey E K et al..
Fibrinolysis in familial pulmonary hypertension.
Am J Clin Pathol.
1979;
71
384-387
- 16
Loyd J E, Primm R K, Newman J H.
Familial primary pulmonary hypertension: clinical patterns.
Am J Rev Respir Dis.
1984;
129
194-197
- 17
Nichols W C, Koller D L, Slovis B et al..
Localization of the gene for familial primary pulmonary hypertension to chromosome
2q31-32.
Nat Genet.
1997;
15
277-281
- 18
Morse J H, Jones A C, Knowles J A et al..
Mapping of familial primary pulmonary hypertension locus (PPH1) chromosome s131-q32.
Circulation.
1997;
95
2603-2606
- 19
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
- 20
Lane K B, Machado R D, Pauciulo J R 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
- 21
Thomson J R, Machado R D, Pauciulo M W et al..
Sporadic primary pulmonary hypertension is associated with germline mutations of the
gene encoding BMPR2, a receptor member of the TGF-β family.
J Med Genet.
2000;
37
741-745
- 22
Trembath J RC, 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
- 23
Du L, Sullivan C C, Chu D et al..
Signaling molecules in nonfamilial pulmonary hypertension.
N Engl J Med.
2003;
348
500-509
- 24
Liu F, Ventura D J, Massague J.
Human type II receptor for bone morphogenetic proteins (BMPR2): extension of the two-kinase
receptor model to the BMPs.
Mol Cell Biol.
1995;
15
3479-3486
- 25
Cogan J D, Vnencak-Jones C L, Pratrap S et al..
Gross BMPR2 gene rearrangements constitute a new cause for primary pulmonary hypertension.
Genet Med.
2005;
7
169-174
- 26
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
- 27
Beppu H, Kawabata M, Hamamoto T et al..
BMP type II receptor is required for gastrulation and early development of mouse embryos.
Dev Biol.
2000;
221
249-258
- 28
Eddahibi S, Fabre V, Boni C et al..
Induction of serotonin transporter by hypoxia in pulmonary vascular smooth muscle
cells: relationship with the mitogenic action of serotonin.
Circ Res.
1999;
84
329-336
- 29
Herve P, Launay J M, Scrobohaci M L et al..
Increased plasma serotonin in primary pulmonary hypertension.
Am J Med.
1995;
99
249-254
- 30
Lee S L, Wang W W, Moore B J et al..
Dual effect of serotonin on growth of bovine pulmonary arterial smooth muscle cells
in culture.
Circ Res.
1991;
68
1362-1368
- 31
Eddahibi S, Humbert M, Fadel E et al..
Serotonin transporter over-expression is responsible for pulmonary artery smooth muscle
hyperplasia in primary pulmonary hypertension.
J Clin Invest.
2001;
108
1141-1150
- 32
Lesch K P, Wolozin B L, Estler H C.
Isolation of a cDNA encoding the human brain serotonin transporter.
J Neural Transm.
1993;
91
67-72
- 33
Loyd J E, Butler M G, Foroud T M et al..
Genetic anticipation and abnormal gender ratio at birth in familial primary pulmonary
hypertension.
Am J Respir Crit Care Med.
1995;
152
93-97
- 34
Rich S, Dantzker D K, Ayres S A et al..
Primary pulmonary hypertension: a national prospective study.
Ann Intern Med.
1987;
107
216-223
- 35
Elliott G, Alexander G, Leppert M, Yeates S, Kerber R.
Coancestry in apparently sporadic primary pulmonary hypertension.
Chest.
1995;
108
973-977
- 36
Newman J H, Wheeler L, Lane K B et al..
Mutations in the gene for bone morphogenetic protein receptor 2 as a cause of primary
pulmonary hypertension in a large kindred.
N Engl J Med.
2001;
345
319-324
- 37
Newman J H, Trembath R, Morse J D et al..
Genetic basis of pulmonary arterial hypertension: current understanding and future
directions.
J Am Coll Cardiol.
2004;
43
S33-S39
- 38
Koehler A, Grunig E, Paucivlo M W 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
- 39
Grunig E, Janssen B, Mereles D et al..
Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary
hypertension gene.
Circulation.
2000;
102
1145-1150
- 40
Wagenvoort C A, Beestri A, Spijker J.
Capillary hemangiomatosis of the lung.
Histopathology.
1978;
2
401-406
- 41
Langleben D, Heneghan J M, Battern A P et al..
Familial pulmonary capillary hemangiomatosis resulting in primary pulmonary hypertension.
Ann Intern Med.
1988;
109
106-109
- 42
Runo J R, Vnencak-Jones C L, Prince M et al..
Familial pulmonary veno-occlusive disease caused by a de novo mutation in BMPR2.
Am J Respir Crit Care Med.
2003;
167
889-894
- 43
Humbert M, Dent Z, Simonneau G et al..
BMPR2 germline mutations in pulmonary hypertension associated with fenfluramine derivatives.
Eur Respir J.
2002;
20
518-523
- 44
Scholand M B, Singh N A, Leppert M et al..
BMPR2 mutations are uncommon in North American patients with appetite suppressant
associated pulmonary arterial hypertension.
Am J Respir Crit Care Med.
2003;
167
A167
- 45
Schneider M D, Gaussin V, Lyons K M.
Tempting fate: BMP signals for cardiac morphogenesis.
Cytokine Growth Factor Rev.
2003;
14
1-4
- 46
Hogan B L.
Bone morphogenetic proteins: multifunctional regulators of vertebrate development.
Genes Dev.
1996;
10
1580-1594
- 47
Roberts K E, McElroy J J, Wong W PK et al..
BMPR2 mutations in pulmonary arterial hypertension with congenital heart disease.
Eur Respir J.
2004;
24
371-374
- 48
Tew M B, Arnett F C, Reveille J D, Tan F K.
Mutations of bone morphogenetic protein receptor type 2 are not found in patients
with pulmonary hypertension and underlying connective tissue diseases [letter].
Arthritis Rheum.
2002;
46
2829-2830
- 49
Morse J, Barst R, Horn E, Cuervo N, Deng Z, Knowles J.
Pulmonary hypertension in scleroderma spectrum of disease: lack of bone morphogenetic
protein receptor-2 mutations.
J Rheumatol.
2002;
29
2379-2381
- 50
Farber H, Loscalzo J.
Pulmonary arterial hypertension.
N Engl J Med.
2004;
351
1655-1665
- 51
Nunes H, Humbert M, Sitbon O et al..
Prognostic factors for survival in HIV-associated pulmonary arterial hypertension.
Am J Respir Crit Care Med.
2003;
167
1433-1439
- 52
Trell E, Johansson B W, Linell F et al..
Familial pulmonary hypertension and multiple abnormalities of large systemic arteries
in Osler's Disease.
Am J Med.
1972;
53
50-63
- 53
Harrison R E, Flanagan J A, Sankelo M 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
- 54
Burke W.
Genetic testing.
N Engl J Med.
2002;
347
1867-1875
- 55
McGoon M, Gutterman D, Steen V et al..
Screening, early detection and diagnosis of pulmonary arterial hypertension: ACCP
Evidence-Based Clinical Practice Guidelines.
Chest.
2004;
126
14S-34S
- 56
Morisaki H, Nakanishi N, Kyuotani S et al..
BMPR2 mutations found in Japanese patients with familial and sporadic primary pulmonary
hypertension.
Human Mutations.
2004;
23
632
C. Gregory ElliottM.D.
Pulmonary Division, Latter Day Saints' Hospital, Eighth Ave. and C St.
Salt Lake City, UT 84143
Email: greg.elliott@ihc.com