Hum Genet (2014) 133:471479

DOI 10.1007/s00439-014-1419-3

Review Paper

The genetic basis ofpulmonary arterial hypertension

LijiangMa WendyK.Chung

Received: 14 October 2013 / Accepted: 7 January 2014 / Published online: 21 January 2014
Springer-Verlag Berlin Heidelberg 2014

Abstract Pulmonary arterial hypertension (PAH) is a rare

disease characterized by distinctive changes in pulmonary
arterioles that lead to progressive elevation of pulmonary
artery pressure, pulmonary vascular resistance, right ventricular failure, and a high mortality rate. The etiology of
PAH is heterogeneous and incompletely understood. Based
on clinical classification, WHO Group 1 PAH includes
sporadic disease (idiopathic PAH), inherited PAH (heritable PAH), and association with certain medical conditions
(associated PAH). Genes play an important role in idiopathic and heritable PAH. Mutations in bone morphogenetic protein receptor 2 (BMPR2), a member of the transforming growth factor (TGF) superfamily of receptors,
have been identified in 70% of cases of familial PAH, as
well as in 1040% of cases of idiopathic PAH. Mutations
in ALK-1, ENG, SMAD4 and SMAD8, other TGF family
members, are additional rare causes of PAH. CAV1 regulates SMAD2/3 phosphorylation, and mutations in CAV1
are a rare cause of PAH. KCNK3 is a member of the twopore domain potassium channels expressed in pulmonary
artery smooth muscle cells, and mutations in KCNK3 are
a rare cause of both familial and IPAH. The genetics of
PAH are complex due to incomplete penetrance and genetic

L.Ma W.K.Chung(*)
Department ofPediatrics, Columbia University, New York, USA
e-mail: wkc15@columbia.edu
L. Ma
e-mail: lm2689@columbia.edu
W.K.Chung
Department ofMedicine, Columbia University, New York, USA
W.K.Chung
1150 St. Nicholas Avenue, Room 620, New York, NY 10032,
USA

heterogeneity. In addition to rare mutations as a monogenic

cause of HPAH, common variants in cerebellin 2 (CBLN2)
increase the risk of PAH by approximately twofold. PAH
in children is much more heterogeneous than in adults and
can be associated with several genetic syndromes, specifically syndromes with congenital heart disease, vascular
disease, and hepatic disease. Clinical genetic testing is
available for PAH and should be considered in families to
allow for more definitive risk stratification and allow for
reproductive planning.

Genetics ofPAH
Pulmonary arterial hypertension (PAH) is a rare disease
characterized by increased pulmonary artery pressure in
the absence of common causes of pulmonary hypertension such as heart, lung, and thrombo-embolic chronic
diseases (Gali etal. 2009). PAH remains a progressive,
fatal disease in many patients despite advances in treatment
(Humbert etal. 2010) with a 1-year incident mortality rate
of 15% (DAlonzo etal. 1991). The pathogenesis of pulmonary arterial hypertension is complex and incompletely
understood, but includes both genetic and environmental
factors that alter vascular structure and function (Humbert
etal. 2010).
Familial cases of PAH have been long recognized (Dresdale etal. 1954) and are usually autosomal dominantly
inherited. The most recent pulmonary hypertension (PH)
classification (4th PH world symposium, Dana Point, 2008)
replaces familial PAH with HPAH at least in part to recognize the fact that 1040% of cases previously thought
to be IPAH harbor identifiable mutations in BMPR2 and,
therefore, pose a hereditary risk to other family members.
Only 6% of PAH patients reported a family history of PAH

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in the prospective National Institutes of Health registry

(Rich etal. 1987). However, a family history of PAH may
go unrecognized in IPAH cases with BMPR2 mutations, as
a consequence of either undiagnosed disease, incomplete
penetrance, or de novo (spontaneous) mutations.
Various strategies that have been used to identify the
PAH associated genes and have evolved as genomic technologies evolved. Initially large families were required
for linkage analysis which mapped PPH1 to chromosome
2q31-q32 (Morse etal. 1997). Positional candidate genes at
2q21-32 were sequenced, and bone morphogenetic protein
receptor type II (BMPR2) was identified as the first major
genetic cause of PAH (International PPH Consortium etal.
2000; Deng etal. 2000a, b). With the advent of whole
exome sequencing, rarer monogenic causes of PAH have
been identified utilizing smaller families than required for
linkage (Austin etal. 2012; Ma etal. 2013). In addition to
identifying rare, monogenic causes of PAH, genome-wide
association study (GWAS) has been successfully applied to
identify common variants predisposing to PAH (Germain
etal. 2013).

BMPR2 andthe TGF family inHPAH

Two laboratories independently mapped the first HPAH
locus, PPH1, to chromosome 2q31-32 (Morse etal. 1997;
Nichols etal. 1997). Fine mapping of the originally large
27cM PPH1 locus narrowed the minimal genetic region
to ~3cM (Deng etal. 2000a, b) thus enabling nucleic acid
sequencing of candidate genes. Two groups independently
and simultaneously identified bone morphogenetic protein
receptor II gene (BMPR2) as the PPH1 gene (Deng etal.
2000a, b; International PPH Consortium etal. 2000).
A mutation in BMPR2 can be identified in ~70% of
HPAH and in ~1040% of IPAH cases (Aldred etal. 2006;
Cogan etal. 2005, 2006; Thomson etal. 2000). BMPR2 is
a member of the transforming growth factor-beta (TGF-)
receptor superfamily.
To date, mutations have been recorded in over 70% of
subjects with one or more affected relatives (Aldred etal.
2007; Machado etal. 2006; Souza etal. 2008; Thomson
etal. 2000). A total of 298 BMPR2 unique mutations have
been identified so far (Machado etal. 2009). The spectrum
of BMPR2 mutations in hereditary and spontaneous disease
is analogous, comprising all major classes of loss of function mutations. Mutations also include larger deletions or
re-arrangements affecting one or more exons or the entire
gene and are not readily detectable by sequencing methods. These mutations were identified in probands, including
those with a known PAH family history, sporadic onset of
disease, and PAH associated with other disorders. All mutations studied to date appear to have independently arisen,

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Hum Genet (2014) 133:471479

suggesting that genetic founder events are uncommon

(Machado etal. 2006).
The TGF- superfamily comprises a large series of
cytokine growth factors that control a host of cellular functions, among them proliferation, migration, differentiation,
apoptosis, and extracellular matrix secretion and deposition. TGF- members are segregated into several subfamilies, which include the prototypic TGF- ligands, receptors,
and accessory molecules, activins, and the largest of these
groups, the bone morphogenetic proteins (Shi and Massague 2003). The implication of BMPR2, ALK-1, ENG,
SMAD4, and SMAD8 as causal factors in hereditary and
associated forms of PAH has emphasized the critical importance of this pathway to the integrity of the pulmonary
vasculature (Harrison etal. 2003) (Fig.1). Heterozygous
germline mutations in activin-like kinase-type I (ALK1)
(Trembath etal. 2001) and Endoglin (ENG) (Chaouat etal.
2004) cause hereditary hemorrhagic telangiectasia (HHT)
and may rarely lead to the development of PAH. HHT is
an autosomal dominant vascular disorder characterized by
the appearance of cutaneous telangiectasias and arteriovenous malformations. Mutations in the SMAD4 gene have
been linked to HHT as well as juvenile polyposis and HHT
(Nasim etal. 2011). A small proportion of HHT patients
have PAH that is clinically and histopathologically indistinguishable from other heritable forms of PAH, while others
have PAH associated with pulmonary arteriovenous fistulas
(Harrison etal. 2003). The underlying causative factor in
these patients is, typically, mutations of ALK-1. Up to 20%
(16/83) of all detected mutations in ALK-1 are associated
with the development of PAH, and, of these, 81% (13/16)
are consistently observed with PAH (Abdalla etal. 2005;
Prigoda etal. 2006). In rare instances, mutations of ALK-1
appear to cause IPAH or HPAH without HHT (Greenwald
etal. 1999; Tew etal. 2002; Trembath etal. 2001).
SMAD8 has also been recently recognized as a possible
cause of PAH (Shintani etal. 2009). One Japanese family
was discovered to have a nonsense mutation in this gene,
leading to a truncated protein (Shintani etal. 2009). Moreover, another BMP receptor BMPR1B (ALK6) is rarely associated with PAH, and two variants in BMPR1B were found
in IPAH patients (Chida etal. 2012).
Mutations in caveolin 1 (CAV1) are a rare cause of PAH,
and two frameshift mutations were identified in both familial cases (frequency 1/62) and IPAH (frequency 1/198)
(Austin etal. 2012). The expression of CAV1 is necessary
for the formation of caveolae, which are 50100nm diameter plasma membrane invaginations and cytoplasmic vesicles presented in numerous cell types including endothelial
and smooth muscle cells of the systemic and pulmonary
vasculature, and type I alveolar cells of the lung. Caveolae are rich in cell surface receptors critical to initiation
of a cellular signaling cascade. CAV1 mutations are loss of

Hum Genet (2014) 133:471479

473

Fig.1Molecular pathogenesis of hereditary PAH. BMP binds to

BMPR2. Upon ligand binding, the type II receptor phosphorylates a
type I receptor, including ALK1, ALK2, ALK3 or ALK6. This leads
to phosphorylation of Smad1/5/8 and phosphorylation of Smad4 with
translocation of the phosphorylated Smads to the nucleus to modulate
the expression of target genes. Upon TGF ligand binding, the TGF
type II receptor phosphorylates a type I receptor, ALK5. This leads to
phosphorylation of Smad2/3which phosphorylate Smad4 and translocate to the nucleus. Endoglin is an accessory membrane glycoprotein that interacts with signaling receptor complexes for the BMP and
TGF- superfamily. Caveolin-1 normally dampens BMP signaling by
inhibiting receptors or their signaling downstream to prevent vascular

proliferation (Maniatis etal. 2008). Lack of caveolin-1 causes activation of STAT3 and ERK1/2 signaling (Mathew etal. 2004), activation
of Ras/p42/44/MAP kinase and upregulation of cyclin D1 (Razani
etal. 2001; Schwencke etal. 2006). Caveolin-1 functions as a tonic
inhibitor of eNOS to facilitate NO mediated relaxation (Razani etal.
2001). Caveolin-1 modifies TGF beta signaling at the plasma membrane which may provide a mechanistic link between CAV1 and
BMPR2 mutations in the pathogenesis of PAH (Austin etal. 2012).
KCNK3 is a potassium channel protein in pulmonary artery smooth
muscle cells. Activation of K+ channel causes K+ efflux, membrane
hyper polarization, and vasodilatation

function mutations resulting in haploinsufficiency. CAV1

directly down regulates Smad2/3 phosphorylation and loss
of CAV1 enhanced Smad2/3 signaling which has been
observed in the lungs of patients with PAH and other types
of pulmonary hypertension, providing a mechanistic link
to the TGF receptor superfamily abnormalities (Phillips
etal. 2008).
The genetics of PAH are complex due to incomplete
penetrance. Almost all hereditary forms of PAH are autosomal dominantly inherited. The majority of families with
HPAH have mutations in BMPR2. The penetrance of the
BMPR2 mutation is low with an estimated lifetime risk
of 20% (Loyd etal. 1995; Rich etal. 1987; Sztrymf etal.
2007). There is an influence of gender on the development
of PAH. Female mutation carriers are about 2.5-fold more
likely to develop FPAH than those of males (Loyd 2002)
with a female to male ratio of 1.7:1 (Larkin etal. 2012).
Some have hypothesized a second genetic hit within the
pulmonary vasculature including epigenetic changes in
Superoxide dismutase 2 (Archer etal. 2010) or somatic
chromosomal abnormalities and quasineoplastic cells

leading to endothelial cell proliferation (Cogan etal. 2006).

One BMPR2 carrier has been shown to have a loss of chromosome 13 in these cells associated with loss of SMAD-8
(Aldred etal. 2010). Alterations in BMPR2 isoform ratios
may provide an explanation of the reduced penetrance
among BMPR2 mutation carriers (Cogan etal. 2012). The
disease is more frequent in adult women, with a ratio of
ranges from 2:1 to 4:1 women to men (Frost etal. 2011;
Humbert etal. 2006). Both incomplete penetrance and the
significantly skewed gender ratio only after puberty suggest
that the BMPR2 mutation alone may not be sufficient to
cause PAH. A second hit which may include other genetic
and/or environmental modifiers of BMPR2 may be necessary to induce development of PAH, indicted by a linkage
study that BMPR2 and the 3q22 locus interact epistatically
(Rodriguez-Murillo etal. 2010). Strong candidates for
modifiers may include sex hormones with altered androgen
to estrogen balance, given the preference of female gender
in PAH and the observation that the majority of women
with PAH are postmenopausal (Scorza etal. 2002; Zamanian etal. 2009). Heterozygous BMPR2 sequence variants

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have been identified in a small subset of patients with PAH

associated with (relatively brief) exposure to fenfluramine
(Humbert etal. 2002; Souza etal. 2008), congenital heart
disease (Roberts etal. 2004), and veno-occlusive disease
(Montani etal. 2008; Runo etal. 2003) raising the question as to whether such factors represent disease triggers in
the face of inherited susceptibility in some patients. In contrast, BMPR2 mutations have not previously been identified
in modestly sized series of PAH associated with the scleroderma-spectrum disease, with human immunodeficiency
virus (Nunes etal. 2003; Tew etal. 2002), Down syndrome
(Greenwood and Nadas 1976), neurofibromatosis 1 (Stewart etal. 2007), Gaucher disease (Lo etal. 2011) or autoimmune polyendocrine syndrome (Alghamdi etal. 2010).

HPAH due toKCNK3 mutations

Mutations in the potassium channel, KCNK3, are a rare
cause of both familial and IPAH (Ma etal. 2013). KCNK3
is a member of the two-pore domain potassium channels
expressed in pulmonary artery smooth muscle cells and
thought to be responsible for setting the resting membrane
potential, responding to hypoxia, and regulating pulmonary
vascular tone (Gurney etal. 2003; Hartness etal. 2001;
Nagaraj etal. 2013; Olschewski etal. 2006; Osipenko
etal. 1997). We identified a novel heterozygous missense
variant c.608 G>A, p.G203D in KCNK3 in a familial PAH
case. We then independently identified five additional heterozygous missense variants (E182K, T8K, Y192C, G97R,
V221L) in 2 of 82 unrelated familial PAH and 3 of 230 idiopathic PAH patients. All six rare variants are novel and
located in highly conserved domains and predicted to be
damaging. Electrophysiological patch clamp studies of the
mutant channels demonstrated that all six missense mutations result in loss-of-function at physiological pH (Ma
etal. 2013). Application of the phospholipase A2 inhibitor
ONO-RS-082 was capable of rescuing channel activity in
some but not all disease associated mutants. This suggests
a potential novel mechanism for therapeutic intervention
by pharmacologically increasing currents through KCNK3
in patients with pulmonary arterial hypertension (Ma etal.
2013).

Autosomal recessive HPAH

Recently, mutations in Eukaryotic Translation Initiation
Factor 2 Alpha Kinase 4 EIF2AK4 were identified in multiple families with pulmonary capillary hemangiomatosis
(PCH)/PAH-associated veno-occlusive disease (PVOD)
(Best etal. 2013; Eyries etal. 2013). All affected subjects
in 14 familial cases carried deleterious homozygous or

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Hum Genet (2014) 133:471479

compound-heterozygous rare variants in EIF1AK4, consistent with autosomal recessive inheritance. Additional
mutation screening by two research teams demonstrated
EIF1AK4 mutations were presented in 5/20 (25%) and
2/10 (20%) of idiopathic cases of PCH/PVOD (Best etal.
2013; Eyries etal. 2013). The protein product of EIF2AK4
belongs to a family of kinases that regulates angiogenesis,
and the alpha subunit of this protein plays a critical role in
induction of angiogenesis, proliferation, and resistance to
apoptosis in stressful environments. EIF2AK4 was found to
interact with SMAD4, SMAD1, ALK-1, endoglin (ENG),
and transforming growth factor- receptor-2 (TGFBR2),
the same signaling network through which BMPR2 acts.
EIF2AK4 mutations are associated with both PVOD and
PCH and further elucidate the underlying molecular genetic
etiology common to the two disease classifications and suggest that perhaps the classification should be revised based
upon underlying etiology.

Genetic complexity ofmonogenic forms ofHPAH

Families with BMPR2 mutations have been reported to
have genetic anticipation, or earlier age of diagnosis in
subsequent generations (Loyd etal. 1995). However, no
systematic population-based study has been performed to
avoid the ascertainment bias that could result in the recruitment and study of families associated with earlier-onset
disease in more recent generations. Furthermore, the usual
genetic mechanisms for anticipation, including trinucleotide repeat expansions, are not present in BMPR2.
Heritable PAH and idiopathic PAH have a similar clinical course. Heritable PAH due to BMPR2 mutations is associated with an earlier age of onset (even in cases without a
family history of PAH) and a slightly more severe hemodynamic impairment at diagnosis: patients with HPAH
had higher mean pulmonary artery pressure, lower cardiac index, and higher pulmonary vascular resistance, but
interestingly had similar survival although they were more
likely to be treated with parenteral prostacyclin therapy or
lung transplant (Sztrymf etal. 2008). Both children and
adults with PAH and BMPR2 mutations are, however, less
likely to respond to acute vasodilator testing during right
heart catheterization and are unlikely to benefit from treatment with calcium channel blockade (Elliott etal. 2006;
Rosenzweig etal. 2008). Symptomatic HPAH patients carrying ALK1 mutations, most without HHT, have an earlier age of onset and more rapid disease progression than
HPAH patients with BMPR2 mutations despite responsiveness to vasodilators at the time of diagnosis (Girerd etal.
2010a, b). There has been controversy over the genotype
phenotype correlations with BMPR2 mutations. Some have
claimed that missense mutations are associated with a more

Hum Genet (2014) 133:471479

severe phenotype than truncating mutations (Austin etal.

2009), but this result has not been replicated (Girerd etal.
2010a, b). At this time, many PAH experts do not routinely
use genetic test results to guide management of the patient
with PAH although the information might suggest the need
for more aggressive therapy and/or earlier consideration of
transplant.

Common variants increase risk ofPAH

In addition to rare mutations as a monogenic cause of
HPAH, a two-stage genome-wide association study
(GWAS) was performed in idiopathic and familial PAH to
identify common variants predisposing to PAH. In a study
with a discovery and confirmation cohort with a total of 625
cases and 1,525 healthy individuals, there was a significant
association at the Cerebellin 2 (CBLN2) locus mapping to
18q22.3, with the risk allele conferring an odds ratio for
PAH of 1.97 (Germain etal. 2013). CBLN2 is expressed
in the lung, with higher expression in explanted lungs from
individuals with PAH and in endothelial cells cultured from
explanted PAH lungs. The hypothesis is that CBLN2 synthesized by endothelial cells might act on vascular SMC
proliferation in a paracrine fashion (Germain etal. 2013).

Pediatric PAH
PAH in children has a wider range of genetic etiologies
than in adults. Pediatric PAH is associated with genetic syndromes with and without congenital heart disease, vascular
disease, and hepatic disease. With all of these syndromes,
PAH is an uncommon complication although in certain
syndromes such as Down syndrome PAH is more common (Nichols etal. 1997). Genetic syndromes more commonly, but not necessarily, associated with CHD and PAH
also include DiGeorge syndrome, VACTERL syndrome,
CHARGE syndrome, Scimitar syndrome (Vida etal. 2010),
Noonan syndrome (Tinker etal. 1989), and chromosomal
anomalies associated with congenital diaphragmatic hernia. Genetic syndromes associated with PAH usually not
associated with CHD include Adams-Oliver syndrome
(Patel etal. 2004; Piazza etal. 2004), Neurofibromatosis
1 (Deng etal. 2000a, b), Long QT syndrome, hypertrophic
cardiomyopathy, Cantu syndrome (Kobayashi etal. 2010)
autoimmune polyendocrine syndrome (International PPH
Consortium etal. 2000), mitochondrial disorders including
mitochondrial encephalopathy lactic acidosis and strokelike episodes (Sproule etal. 2008) Gaucher disease (Deng
etal. 2000a, b), and glycogen storage diseases (GSDI and
GSDIII) (Lee etal. 2011). The mechanism for development

475

of PH has not been definitely demonstrated for most

genetic syndromes but could involve increased pulmonary
blood flow with left to right shunts with CHD, pulmonary
venous obstruction (Cantu syndrome) (Kobayashi etal.
2010) or production of diffusible hepatic factors increasing
the pulmonary pressures (Gaucher disease and GSD) (Lee
etal. 2011). For all of these genetic disorders a common
question is why the majority of patients with these disorders never develop PAH and what is different about those
who do.

Genetic testing forPAH

Clinical genetic testing is available for PAH for BMPR2,
ALK1, ENG, SMAD8, and CAV1 genes including both
sequencing and deletion/duplication testing. Genetic testing is available for either single genes or the entire panel
of genes. The cost of testing has recently decreased in the
US with the introduction of these gene panels, increasing
the accessibility of testing to patients. Genetic testing is
often considered in pediatric PAH to explain the etiology
of the disease and counsel family members about identifying other family members at risk and accurately determining the risk of recurrence in future children. The most
commonly cited reasons for genetic testing for PAH is to
provide information to and about children (Jones etal.
2008). Pre-implantation genetic diagnosis has been used to
avoid transmission to offspring once the familial mutation
was identified (Frydman etal. 2012).
Using the combined approaches of sequencing and deletion duplication analysis, approximately 75% of HPAH
patients will have an identified mutation in a PAH gene,
most commonly in BMPR2 (Machado etal. 2001). Clinical
genetic testing is available in North America and Europe,
with the current cost of testing usually covered by insurance with results generally available in 8weeks. Once the
mutation in a family is known, testing other family members for a family-specific mutation in US is relatively inexpensive, accurate, and fast. As a consequence of the incomplete penetrance and variable age of onset, identification of
a BMPR2 mutation may have a complex and serious psychosocial impact on the family and is often associated with
feelings of guilt in the parent who has passed on mutations
to the children. Genetic testing is most helpful when it is
able to identify members of the family who are not genetically at risk for PAH, and who can then forgo the otherwise
recommended serial evaluations to screen for development
of PAH. For at-risk family members, regular screening by
echocardiogram every 3years and awareness of disease
symptoms should enable early diagnosis and treatment
which may improve outcomes.

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Conclusion
The genetics of pulmonary hypertension are complex.
While loss-of-function mutations of some genes, such as
BMPR2, have been established as major monogenetic risk
factor for PAH, their disease penetrance is modest, suggesting other genetic or environmental modifiers. The skewed
gender ratio for IPAH and HPAH after puberty suggests
that these modifiers may be gender specific and could be
related to hormonal differences. Genetic testing is available
for PAH and should be considered in families to identify
individuals who are at increased risk of developing PAH.
Positively tested individuals will undergo close clinical follow-up for PAH development and may make reproductive
decisions based upon an increased risk of recurrence.
Acknowledgments This work was supported by R01 HL060056.

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