DETECTION OF MUTATIONS IN THE CYP21A2 GENE:
GENOTYPE-PHENOTYPE CORRELATION IN
SLOVENIAN COUPLES WITH CONCEIVING PROBLEMS
Stangler Herodež Š1,*, Fijavž L2, Zagradišnik B1, Kokalj Vokač N1,2
*Corresponding Author: Dr. Špela Stangler Herodež, Laboratory of Medical Genetics, University Clinical
Centre Maribor, Ljubljanska ulica 5, 2000 Maribor, Slovenia. Tel: +386-2-321-27-37. Fax: +386-2-321-27-55.
E-mail: spela.sh@ukc-mb.si
page: 25
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DISCUSSION
In our research, we determined the frequency of
the c.290-13A/C>G, p.I172N, p.P30L and p.V281
mutations in couples with conceiving problems comparing
them with a healthy control group. We did not
observe any statistical differences between frequency
of heterozygous carriers in infertile couples and HCs.
Although we did not find any statistically important
association, we cannot exclude the importance of
the aforementioned mutations in infertility. We attribute
it to an insufficient number of test subjects and
controls. Also, we cannot draw an indefinite conclusion,
as the presence of mutations in the CYP21A2
gene may be associated with infertility [16]. It is
also important to point out that in samples without
the c.290-13A/C>G, p.I172N, p.P30L and p.V281
mutations, we cannot exclude the presence of other
mutation variants in the CYP21A2 gene [17].
In female test subjects, we examined the hormonal
profiles during stages of the menstrual cycle
and determined concomitant diagnosed illnesses from
available medical documentation. We did not find any
statistically significant association between hormonal
deviations, concomitant illnesses and mutation frequency.
However, we can conclude that the presence
of a single mutation in the CYP21A2 gene does not
distinctively affect the hormonal status [9,18].
In general, fertility in people with CAH ranges
from normal to severely impaired, as Reichman et al.
[19] found that most CAH patients encountered fertility
issues. In addition, these patients had less successful
natural conceptions with more patients reporting
spontaneous abortions. Similarly, Reichman et al.
[19] found the frequency of successful conceptions is
inversely proportional to the severity of mutations. To
explain, females with an evidently more significant
structural anomaly encountered more difficulties in
conception [7,8,19]. Moreover, structurally milder
mutations did not significantly affect fertility.
Çakir et al. [20] found that males with CAH have
an evident diminished reproductive capability due to
the presence of hipogonadotropic hipogonadism and
consequently testicular adrenal rest tumors (TART).
The latter, being more common, have adrenocorticotropic
hormone (ACTH) and angiotensin II receptors
and they synthesize similar steroid hormones as
the adrenal glands. Permanent localized high steroid
concentration may in turn damage the testes [16,20].
Peritubular testicular fibrosis results in impaired spermatogenesis
[21]. In addition, the size of TART is
inversely proportional to testosterone production and
sperm ejaculation count [22].
We also studied the association between mutations
in CAH and most frequently found concomitant
illnesses. We did not find any association between
female test subjects and the frequency of associated
illnesses. Deckx et al. [23] found estrogens and
progesterins to have immunomodulatory properties.
In addition, Gleicher et al. [24] found that infertile
females not only possess a diminished ovarian reserve
but also serological profiles associated with
autoimmune diseases. Moreover, he implicates an
existence of an androgen derived cofactor, responsible
for immunologic disorders [24]. In our study,
we did not find any statistically significant association
between the presence of a mutation and the level of
testosterone in female subjects.
The CYP21A2, RP, C4 and TNX genes are
structurally adjacent, thus forming a genetic module
RCCX complex. Olsson and Holmdahl [25] determined
that CAH is closely associated with autoimmunity.
Chen et al. [26] found that a mutation in the
CYP21A2 gene results not only in 21-OH deficiency
but also in a variable copy count of the C4 gene. To
clarify, the C4 gene encodes a homonymous protein,
involved in classic complement activation [26]. In
our study, we did not find a statistically significant
association between autoimmunity and our studied
mutations.
Thyroid disorders are closely associated with infertility.
They not only affect female fertility but also
hinder most of the human organs [27,28]. Sinha et al.
[29] found that in thyrotoxicosis there is an increase
of all sex hormones and their plasma binding proteins.
As mentioned, excess estrogens hamper conception
and pregnancy [2,10, 29]. Mansourian [30] and Mnif
et al. [11] found that pathologic hormonal profiles of
women with hyper- and hypothyroidism often result
in abortions, low birth weight and premature labor.
In our study, we did not find any association between
mutations in the CYP21A2 gene and the presence of
thyroid disease.
On the other hand, we found an association between
the p.V281L mutation in the CYP21A2 gene
and a marker indicating any hormonal deviance (p =
0.008). Next, we also found an association between
the p.V281L mutation in the CYP21A2 gene and the frequency of PCOS (p = 0.000). Although we found
this association, we cannot categorically confirm an
actual association due to the small number of enrolled
test subjects.
Surprisingly, we did not find a firm association
between mutations and deviance in hormonal
profiles. Of course, our results do not disprove that
the c.290-13A/ C>G, p.I172N, p.P30L and p.V281L
mutations in the CYP21A2 gene are involved in infertility.
Further research is necessary in order to
clarify whether CAH is involved in infertility. According
to Montgomery et al. [31], genome-wide
association studies (GWAS) represent an evolution
in polymorphism, mutation and gene research. Broad
population GWAS, using multiple gene markers and
extensive clinical information will be important in
helping clinicians in not only disease treatment but
also in predicting the risk of concomitant disease
occurrence [29,31].
Whether it is necessary to enroll all couples diagnosed
with infertility in genetic counseling, is still
debatable. Many studies confirm the necessity of
such a protocol, as there is a confirmed higher incidence
of gene mutations among these couples [32].
Conversely, Papanikolaou et al. [33] disagrees with
mandatory genetic testing of couples with infertility.
He proposed that genetic testing should be executed
only upon a valid indication.
In conclusion, does an early diagnosis of CAH
essentially reduce the consequence of CAH? Moreover,
should we be actively screening the population
for mutations in the CYP21A2 gene? To date, in the
USA and 40 other countries, screening of CAH is
done at birth [34]. The multitude of disease manifestations
develop with age, therefore, in order to
minimize disease outcomes, many stress the necessity
of early detection of CAH [35,36].
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