J Appl Physiol 119: 1481–1486, 2015.

First published August 13, 2015; doi:10.1152/japplphysiol.00271.2015. Review

HIGHLIGHTED TOPIC Hypoxia 2015

New genetic and physiological factors for excessive erythrocytosis and

Chronic Mountain Sickness
Francisco C. Villafuerte
Laboratorio de Fisiología Comparada, Facultad de Ciencias y Filosofía, Universidad Peruana Cayetano Heredia, Lima, Perú
Submitted 7 April 2015; accepted in final form 7 August 2015

Villafuerte FC. New genetic and physiological factors for excessive erythrocy-
tosis and Chronic Mountain Sickness. J Appl Physiol 119: 1481–1486, 2015. First
published August 13, 2015; doi:10.1152/japplphysiol.00271.2015.—In the last few
years, genetic and functional studies have provided important insight on the
pathophysiology of excessive erythrocytosis (EE), the main sign of Chronic
Mountain Sickness (CMS). The recent finding of the association of the CMS
phenotype with a single-nucleotide polymorphism (SNP) in the Sentrin-specific
Protease 1 (SENP1) gene, and its differential expression pattern in Andean
highlanders with and without CMS, has triggered large interest in high-altitude
studies because of the potential role of its gene product in the control of erythro-
poiesis. The SENP1 gene encodes for a protease that regulates the function of
hypoxia-relevant transcription factors such as Hypoxia-Inducible Factor (HIF) and
GATA, and thus might have an erythropoietic regulatory role in CMS through the
modulation of the expression of erythropoietin (Epo) or Epo receptors. The
different physiological patterns in the Epo-EpoR system found among Andeans,
even among highlanders with CMS, together with their different degrees of
erythropoietic response, might indicate specific underlying genetic backgrounds,
which in turn might reflect different levels of adaptation to lifelong high-altitude
hypoxia. This minireview discusses recent genetic findings potentially underlying
EE and CMS, and their possible physiological mechanisms in Andean highlanders.
Chronic Mountain Sickness; excessive erythrocytosis; chronic hypoxia; high alti-
tude; Andes

IN THE LAST FEW YEARS, GENETIC and functional studies have
provided important insight into the pathophysiology of exces-
sive erythrocytosis (EE) and Chronic Mountain Sickness
(CMS). The use of genomic technologies has allowed the
identification of functionally relevant single-nucleotide poly-
morphism (SNPs) as markers of “maladaptation” to life at high
altitude, as well as some potential functional correlates. This
minireview discusses recent genetic findings potentially under-
lying EE and CMS, and their possible physiological mecha-
nisms among residents of the Andean highlands.
CHRONIC MOUNTAIN SICKNESS OR MONGE DISEASE
CMS is a clinical syndrome characterized by EE, which is
defined by hemoglobin (Hb) concentration values ⱖ21 g/dl for
men or ⱖ19 g/dl for women (30). CMS is diagnosed on the
basis of the presence of EE accompanied by three or more of
the following symptoms: breathlessness, palpitations, sleep
disturbance, cyanosis, dilation of veins, paresthesia, headache,
or tinnitus (29, 33, 39) according to the Qinghai International
Address for reprint requests and other correspondence: F.C. Villafuerte,
Laboratorio de Fisiología Comparada, Facultad de Ciencias y Filosofía, Uni-
versidad Peruana Cayetano Heredia, Av. Honorio Delgado 430, Lima 31,
Lima, Peru (e-mail: francisco.villafuerte@upch.pe).
http://www.jappl.org 8750-7587/15 Copyright © 2015 the American Physiological Society
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Consensus scoring system (30). Pulmonary hypertension is a
frequent complication of the condition and may lead to right-
heart failure in advanced stages of the disease (42, 43). CMS
affects people who reside at altitudes ⱖ2,500 m above sea
level, and it is estimated that 5-10% of the world’s population
living at high altitude may develop the condition (13, 21, 30,
48, 51). In the central Andes of Peru (⬎4,000 m), 15–20% of
the adult male population suffers from CMS, and its prevalence
increases with age, rising up to 30% by the age of 50 (29, 39).
The pathophysiological mechanism of EE is still debatable;
however, it is well known that hypoxemia represents its un-
derlying stimulus because relocation of patients with CMS to
sea level reverses the disorder completely. Also, it has been
shown that phlebotomy, with or without isovolemic hemodi-
lution, alleviates CMS-related symptoms, suggesting that
many of these are associated with EE (37, 46, 57, 58).
A POTENTIAL GENETIC MARKER FOR EXCESSIVE
ERYTHROPOIESIS
Although it has been known for some time that high Hb
concentration values among Andean highlanders show herita-
bility and familial character (4, 31), until recently no specific
alleles had been found to be associated with the exaggerated
red blood cell count in patients with CMS. Recent studies have
1481
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1482 Genetics and Physiology of Excessive Erythrocytosis and CMS • Villafuerte FC

revealed that specific SNPs in the EPAS1 and EGLN1 genes are
associated with low Hb concentration values in Tibetan high-
landers and suggest that these markers may be linked to a
physiological mechanism that confers protection to this popu-
lation against the development of EE and CMS (5, 49, 62). The
products of these genes, Hypoxia-Inducible Factor-2 (HIF-2)
and Prolyl Hydroxylase Domain 2 (PHD2), respectively, are
major regulators of erythropoiesis given their central role in the
control of the hypoxic response of erythropoietin (Epo) expres-
sion at the transcriptional level. However, among Andeans, no
such “protective” alleles have been identified, and no differ-
ences in the frequencies of these SNPs between healthy high-
landers and those with CMS have been demonstrated (31).
Differences are also absent in other candidate genes associated
with erythropoiesis, such as Epo and Epo receptor (EpoR).
The recent finding of an association of the CMS phenotype
among Andeans with an SNP in the sentrin-specific protease 1
(SENP1) gene has triggered large interest in the field of
high-altitude studies because of the potential role of its gene
product in the control of erythropoiesis (7, 47, 66). The
identified candidate gene was validated by hypoxic functional
testing in cultured fibroblasts derived from skin biopsies ob-
tained from the same subjects. Compared with normoxic con-
trols, hypoxia treatment (1.5% O2 for 24 h) induced a signif-
icant downregulation of SENP1 expression in non-CMS cells
and an upregulation in CMS cells (66). Therefore, it is likely
that the lower arterial O2 saturation in patients with CMS
induces a higher expression of SENP1 and favors exaggerated
erythropoiesis. Thus in contrast with Tibetans and Ethiopians,
Andeans show a proerythropoietic SNP rather than protective
SNPs against erythrocytosis. This supports the hypothesis of
different degrees of high-altitude adaptation among popula-
tions. It would be interesting to explore whether the SENP1
SNP found in Tibetans and Ethiopians correspond to the
“adapted variant” of the SENP1 allele found in healthy Andean
highlanders.
PHYSIOLOGICAL CORRELATES TO THE CANDIDATE GENE
SENP1
SENP1 plays important roles in the regulation of multiple
cellular signaling pathways, including glucose and mitochon-
drial metabolism, and hormone receptor activity regulation (1,
6, 9, 11, 34, 52, 60). Also, studies in animal models show that
SENP1 plays a key function in normal erythropoiesis. But is
there a potential link between SENP1 and the pathophysiolog-
ical erythropoietic response? SENP1 is a small ubiquitin-
related modifier (SUMO) protein-specific protease that regu-
lates the function of hypoxia-relevant transcription factors such
as HIF and GATA (8, 65). SENP1 deconjugates the SUMO
from HIF1␣ and rescues this subunit from ubiquitination and
degradation (Fig. 1). Studies in mouse embryos have shown
that SENP1 is required for hepatic Epo production and eryth-
ropoiesis, and that senp1⫺/⫺ mice die from anemia (8). Thus
although this pathway has not been yet verified in humans, it
seems likely that SENP1-dependent regulation of HIF2␣, the
main erythropoietic HIF␣ isoform in adults, shares similar
direct and indirect regulatory pathways with HIF1␣ (8, 25).
In addition, SENP1 regulates erythropoiesis via GATA-1
deSUMOylation (65). Consistently, GATA1-null mouse em-
bryos die from severe anemia (15). The critical role of GATA1
in erythropoiesis is attributed to its activity in driving expres-
sion of many erythropoietic genes including enzymes involved
in heme biosynthesis, hemoglobin, and EpoR (10, 17, 26, 67).
Among these, EpoR expression has been well established to be
critical for definitive erythropoiesis in murine fetal liver (28,
35, 59). Yu et al. (65) showed that a SUMOylated form of
GATA1 accumulated in senp1⫺/⫺ mice and correlated with a
downregulation of GATA1-dependent gene expression includ-
ing EpoR and ␤-hemoglobin. The study also showed that
GATA1 can be directly deSUMOylated by SENP1, resulting in
the modulation of GATA1-dependent EpoR expression and
erythropoiesis.

Fig. 1. Schematic model of sentrin-specific protease 1

(SENP1) on Hypoxia-Inducible Factor ␣ (HIF␣) and
GATA-1 regulation. A: under normoxia, HIF␣ is sub-
ject to oxygen-dependent prolyl hydroxylation by
Prolyl-Hydroxylase Domain-containing enzymes
(PHDs), which allows for substrate recognition and
ubiquitylation by Von Hippel-Lindau protein (pVHL)
and its associated ubiquitin-ligase complex. Polyubiq-
uitylated (Ubn) HIF␣ is then degraded by the protea-
some. B: under hypoxia, HIF␣ escapes prolyl hydroxy-
lation and undergoes SUMOylation. SENP1-dependent
deSUMOylation rescues HIF␣ from polyubiquitination
and degradation, and allows its association with nuclear
HIF␤. The heterodimer binds to a core consensus se-
quence at the promoters of HIF-responsive genes, and
upon binding to coactivators, initiates transcription.
SENP1-dependent GATA-1 deSUMOylation enhances
its transcriptional activity, and thus upregulation of
SENP1 expression might increase available deSUMOy-
lated GATA-1 and enhance gene transcription. OH,
hydroxyl group; Ub, ubiquitin moiety.

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Genetics and Physiology of Excessive Erythrocytosis and CMS
It is interesting that these two SENP1 targets, HIF and
GATA, control the Epo-EpoR system, and thus it is likely that
hypoxic SENP1 upregulation as shown in patients with CMS
(66) alters the Epo-EpoR system and therefore erythropoiesis.
ARE THERE ANY OTHER POTENTIAL FUNCTIONAL
CORRELATES TO SENP1-INCREASED EXPRESSION IN CMS?
HIF-mediated hypoxic expression of genes such as VEGF
might be enhanced by SENP1 due to deSUMOylation and
increased HIF␣ subunit stability (8). Apenzeller and coworkers
(2) showed that VEGF expression was increased in patients
with CMS, and it was positively correlated with CMS score
and negatively with arterial saturation. More recently, Xu et al.
(61) have provided evidence that SENP1 plays an essential role
as a positive regulator of hypoxia-driven VEGF production and
angiogenesis by showing that silencing of SENP1 expression
decreases VEGF production and abrogates the angiogenic
functions of endothelial cells. Therefore, there is a possibility
that an increased SENP1 expression in CMS relates to changes
in the expression of VEGF.
THE Epo-EpoR SYSTEM AND ITS PHYSIOLOGICAL
ASSOCIATION WITH EE
The role of SENP1 in erythropoiesis supposes HIF and
GATA stabilization with the consequent expression of target
genes. SENP-dependent (direct or indirect) stabilization of
HIF2␣ would lead to increased Epo expression and increased
erythropoiesis, similarly to what is observed in other condi-
tions with augmented HIF2␣ levels (27, 44). However, ele-
vated blood Epo values are not common in patients with CMS.
Most highlanders with CMS exhibit EE but normal Epo values
for the altitude of residence, similar to those observed in their
healthy counterparts (16, 23, 32). Yet a subgroup of patients
with CMS show significantly higher Epo values (2 SD above
the altitude-normal average) usually with slightly higher Hb
(12, 32, 53) (Table 1). This finding might help explain why
most studies, but not all, report normal Epo average values in
CMS (16, 23, 32, 45, 53), because these values would depend
on the proportion of participants with normal and high Epo
values. Moreover, given that increased SENP1 expression
supposes increased Epo expression, it would be important to
question whether the strength of the association between the
SENP1 polymorphism and the CMS phenotype remains the
same when the proportion of highlander participants with high
Epo is changed. This is definitely an aspect that must be taken
into consideration in future research. The remarkable differ-
ence in Epo levels between the two subgroups of patients with
CMS suggests underlying genetic differences.
Table 1. Characteristics of sea-level residents, healthy highlanders, and patients with CMS
Sea-Level Residents
Hb, g/dl 14.5 ⫾ 0.2
CMS score 1.4 ⫾ 0.3
Arterial O2 saturation, % 98.3 ⫾ 0.2
Epo, pg/ml 23.6 ⫾ 1.0
CMS, Chronic Mountain Sickness; Epo, erythropoietin. Sea-level residents (n ⫽ 25), healthy highlanders (n ⫽ 44), normal-Epo CMS (n ⫽ 32), and high-Epo
CMS (n ⫽ 10). Values are means ⫾ SE. Significance aP ⬍ 0.01 vs. sea-level residents, bP ⬍ 0.001 vs. sea-level residents, cP ⬍ 0.001 vs. healthy highlanders,
d
P ⬍ 0.001 vs. normal-Epo CMS. Data from (53).
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• Villafuerte FC 1483
IS IT POSSIBLE THEN TO EXPLAIN AN INCREASED
PRODUCTION OF RED BLOOD CELLS WITH NORMAL Epo
VALUES?
Epo action depends both on Epo concentration and on the
abundance and type of Epo receptors (24, 50). Thus modula-
tion of EpoR expression or differential regulation of expression
of EpoR splice variants represents a potential erythropoiesis
regulatory mechanism. SENP1-mediated regulation of EpoR
expression is likely to occur through GATA-1. The 5=-flanking
region of the EpoR gene has several potential GATA-1 binding
sites and EpoR expression is regulated by promoters that bind
to GATA-1 (64, 65, 67). Also, it has been demonstrated that
this regulation is specific for cells of the hematopoietic line
(63).
In addition to EpoR gene expression modulation, the ex-
pressed proportion of splice variants of the gene can also affect
the sensitivity of the system to Epo. EpoR can be synthesized
in several forms: full-length, truncated, and soluble. Exons 1 to
5 encode the extracellular domain, exon 6 encodes the mem-
brane-spanning domain, and exons 7 and 8 encode the intra-
cellular domain (20). The soluble receptor form (sEpoR) with
a molecular weight of 29 kDa corresponds with the extracel-
lular domain of the complete membrane EpoR (mEpoR) (18,
41, 56), and its synthesis occurs by alternative splicing of EpoR
mRNA (14, 19, 56). Recent findings suggest that the sEpoR
plays a role in modulating Epo action in patients with CMS
(53).
Although it is likely that genetic variation at the splicing
machinery level has a significant effect on the abundance of
membrane-bound or soluble Epo receptors, SUMOylation of
spliceosome factors might also play an important role. Pro-
teomic analysis has revealed that SENP isoforms are key in the
deSUMOylation and function of these factors (55). Thus in
addition to the role of SENP1 in EpoR expression via
GATA-1, it has also a potential role modifying the splicing
machinery and therefore the production of EpoR isoforms.
Functionally, several studies have shown that the binding
of Epo to sEpoR limits its ability to bind mEpoR (3, 38, 50),
and thus this soluble isoform acts as an Epo “buffer”
regulating available circulating Epo concentration. Our
group has recently shown that EE is strongly associated with
low circulating sEpoR values and high Epo-to-sEpoR ratios
(Epo/sEpoR), leading to elevated plasma Epo availability,
and thereby a stronger stimulus for erythropoiesis (53) (Fig. 2).
For this reason, when comparing healthy highlanders and those
with CMS with low and high Epo levels, Hb concentration
shows an exponential rise with increasing Epo/sEpoR ratio
values, reaching the highest level in the high Epo group.
Healthy Highlanders Normal-Epo CMS High-Epo CMS
17.7 ⫾ 0.2 b
22.2 ⫾ 0.2b,c
24.2 ⫾ 0.8b,c,d
2.7 ⫾ 0.4a 7.2 ⫾ 0.9b,c 8.0 ⫾ 1.4b,c
88.2 ⫾ 0.6b 84.4 ⫾ 0.7b,c 82.5 ⫾ 1.1b,c
37.8 ⫾ 1.9b 43.5 ⫾ 2.4b 87.1 ⫾ 8.4b,c,d
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1484 Genetics and Physiology of Excessive Erythrocytosis and CMS
Fig. 2. Plasma soluble Epo receptor (sEpoR) and the relationship between
hemoglobin (Hb) and the Epo-to-sEpoR ratio among highlanders and patients
with Chronic Mountain Sickness (CMS). A: plasma sEpoR concentration in
healthy highlanders and individuals with CMS with normal and high plasma
Epo concentration (normal Epo CMS and high-Epo CMS, respectively) at high
altitude. Bars are means ⫾ SE. *P ⬍ 0.05, ***P ⬍ 0.001. B: relationship
between Epo/sEpoR and Hb concentration. The figure shows nonlinear best-fit
for mean Hb values as a function of mean Epo/sEpoR, including sea level
residents, healthy highlanders, and patients with normal Epo and high Epo
CMS. Values are means ⫾ SE.
At present, information does not exist on the effect of
lifelong chronic hypoxia exposure on sEpoR. However,
experiments in mice have shown that sEpoR expression can
be downregulated by prolonged exposure to hypoxia (33).
Changes in alternative splicing of several genes have been
reported as a physiological response to hypoxia, whether by
upregulating or downregulating splice isoform expression
(54). The fact that the accentuated hypoxemia in patients
with CMS and normal Epo compared with healthy highland-
ers is not associated with higher plasma Epo but with
decreased sEpoR concentration suggests that chronic hyp-
oxia affects Epo and sEpoR in CMS in differential manners.
Whether reduced blood sEpoR levels result from a chronic
downregulation of sEpoR production at the mRNA splicing
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• Villafuerte FC
machinery level caused by the chronically lower arterial O2
saturation in patients with CMS or from genetic differences
has yet to be clarified. Also, it is unknown whether differ-
ential expression of the splice EpoR isoforms, sEpoR mE-
poR, contributes to increased Epo action in persons with
similar Epo values, and also whether factors such as SENP1
are involved in EpoR expression and the balance between
mEpoR and sEpoR. It is possible that reduced sEpoR levels
in CMS are accompanied by increased levels of its mem-
brane counterpart leading to increased sensitivity to Epo in
addition to increased Epo availability. Finally, EpoR expres-
sion and the relative abundance of its splice isoforms also
might be influenced by epigenetic factors. Several studies
have suggested that perinatal hypoxia, for example, predis-
poses highlanders to develop EE and CMS during adulthood
(22, 23, 36, 40). Whether perinatal hypoxia or other envi-
ronmental factors affect the Epo-EpoR system is one im-
portant aspect that must be considered in future research.
The different physiological patterns in the Epo-EpoR system
among Andean highlanders together with their different de-
grees of erythropoietic response might indicate specific under-
lying genetic backgrounds, which in turn, might reflect differ-
ent levels of adaptation to chronic high-altitude hypoxia. Pa-
tients with CMS and high Epo, with their exaggerated
erythrocytosis and elevated plasma Epo, could be regarded as
the least adapted, followed by highlanders with CMS and
normal Epo, with still excessive but lower Hb and normal
circulating Epo concentration, and finally healthy Andeans,
with a modestly elevated Hb and normal Epo values for the
altitude of residence, as the most adapted among groups within
the same population.
Therefore, functional and phenotypic differences between
healthy Andean highlanders and those with CMS, and even
among patients with CMS, suggest the involvement of
multilevel physiological control points, each with a poten-
tial specific combination of genetic variants. These variants
would ultimately determine the presence and severity of EE
and the degree of maladaptation to chronic high-altitude
hypoxia.
ACKNOWLEDGMENT
I thank Noemi Corante for helpful comments and manuscript
editing.
GRANTS
Support for this study was provided by Wellcome Trust Public Health and
Tropical Medicine Fellowship 097275/Z/11/Z.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author.
AUTHOR CONTRIBUTIONS
F.C.V. conception and design of research; F.C.V. performed experiments;
F.C.V. analyzed data; F.C.V. interpreted results of experiments; F.C.V. drafted
manuscript; F.C.V. edited and revised manuscript; F.C.V. approved final
version of manuscript.
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