STUDY OF THREE SINGLE NUCLEOTIDE
POLYMORPHISMS IN THE SLC6A14 GENE
IN ASSOCIATION WITH MALE INFERTILITY
Noveski P1, Mircevska M1, Plaseski T2, Peterlin B3, Plaseska-Karanfilska D1,*
*Corresponding Author: Dijana Plaseska-Karanfilska, M.D., Ph.D., Research Centre for Genetic Engineering
and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000
Skopje, Republic of Macedonia. Tel. +389-2-3235-410. Fax: +389-2-3115-434. E-mail: dijana@manu.edu.mk
page: 61
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INTRODUCTION
Spermatogenesis is a complex biological process
that involves mitosis, meiosis and spermiogenesis, that
are under endocrine and paracrine regulation [1]. Many
genes are specifically transcribed only during these
processes and reduction or absence in their expression
could lead to infertility or subfertility. Well-known
genetic causes of male infertility include sex chromosome
aneuploidies, Y chromosome AZF microdeletions
and mutations in the CFTR and AR genes [2,3],
but 60.0-75.0% of patients with male infertility appear
to be idiopathic [4]. Besides genes that are directly
involved and expressed during spermatogenesis in
testicular tissue, others are ubiquitously transcribed
during normal functioning of cells and genetic variation
and impairment in their expression could lead to
disruption of spermatogenesis. Pleiotropy, in which a
gene has an effect on multiple phenotype traits [5] and
variation in the gene could lead to different effects on
each of these, is also possible. Moreover, genetic variation
in several genes could combine as low-penetrant
risk alleles and contribute to the phenotype outcome.
We have previously investigated the association
of nine single nucleotide polymorphisms (SNPs) in
eight different genes with idiopathic male infertility
on the basis of one genome-wide association study
[6]. Our findings confirmed the association of SNPs
rs5911500 in LOC203413, rs3088232 in BRDT and
rs11204546 in OR2W3, in oligo-zoospermic and azoospermic
men with infertility and of different ethnicity
(Macedonians and Albanians) [7]. A minor allele
of rs5911500 in LOC203413 retained strong association
when we enlarged the group to include Slovenian
males. This SNP on the long arm of chromosome X
(Xq23) is in close proximity to the SLC6A14 (NM_
007231.4) gene, which is a member of the solute
carrier family 6 that transports neutral and cationic
amino acids in a sodium- and chloride-dependent
manner. It contains 14 exons and spans 29 kb [8].
The SNPs in this gene have been associated with
obesity [9-11] and meconium illeus (a known clinical
manifestation of cystic fibrosis) [12]. There is also
evidence of pleiotropic effects of the SLC6A14 gene
in other CF-related morbidities [13]. The SLC6A14
gene has high affinity for several amino acids, including
tryptophan [8], and could be involved in regulation
of tryptophan availability for serotonin synthesis
[9]. In fact, serotonin has been shown to be necessary
for normal spermatogenesis in prepubertal rats [14].
An association has also been demonstrated between
serotonin and testosterone production [15], and between
testicular blood flow and vasomotion [16] in
rats. This study investigated the possible association
of three SNPs (rs2312054, rs2071877 and rs2011162)
in the SLC6A14 gene with idiopathic male infertility.
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