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A New Approach to Genetic Factors of Men’s
Infertility: A Case Study
Ali Saeeidi
Department of Human Genetics, Andhra University, Entrance Rd, Visakhapatnam, Andhra Pradesh, India
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ccording to the definition of World Health Organization, infertility is inability of couples in productivity after one year of sexual intercourse without any prevention [1-8].
Infertility is one the most prevalent problems in the world which is seen in about 15% of couples [9, 10]. Depending on the sex type, there are different factors which can be effective in infertility [11-15]. For women, these factors are including endometriosis, ovulation problems, low quality of ovum, pol- ycystic ovary syndrome and blockage of Fallopian tubes [16-
23]. However, these factors for men are blockage of vas, sperm problems (low number, low mobility, dis-morphology) and sperm allergy [24]. In addition, some percent of infertility cas- es are related to unexplained factors of infertility [25, 26].
Male factor is effective in half of the infertility cases. The presence of male factor is frequently based on the unnatural sperm parameters (azoospermia to oligozoospermia) [27]. Generally, the infertility factors are in three types: acquisitive, congenital and unexplained factors [28-30]. Congenital factors may be originated genetically or produced from genetic mal- formation. In spite of vast studies to find the natural origina- tion of infertility in men, unexplained factors are mostly rec- ognized as the origin of infertility in men [31-38]. It is suggest- ed that the infertility may be resulted from mutations and or other changes in genes of spermatogenesis [39, 40].
The prevalence of chromosomal malformations among sterile men is high and degree of malformation is conversely related to the number of sperms. According to the published results, the general frequency of chromosomal factors is between 2 and 8 % with average of 5 %. However, it can be raised up to
15 % in azoospermia men which mostly are XXY men [41]. The malformation of chromosome Y such as microdeletion is the important factor of azoospermia cases and sever oligozoo- spermia cases (number of sperms as low as 20 million per m.litre) [42-43].
Aneuploidy is the most frequent reason of chromosomal
malformation among sterile men [44]. Particularly, men with non-blockage azoospermia are more subjected to aneuploidy [45], especially in sexual chromosomes [46]. Although an an- euploid sperm is of changed genetic materials, it can be suc- cessfully inseminate the ovum and transported uncorrected number of chromosomes to offspring [47].
Klinefelter syndrome and Mozaism of XXY: Klinefelter syndrome is the most prevalent aneuploid sexual chromosome in men so that it is happened in 0.1 to 0.2 % of new births. The frequency of the syndrome is very high in sterile men between
5 % in sever oligospermia to 10 % in azoospermia cases. The syndrome is a type of primary deficiencies of testicle along with hypertrophy of testicle and the increase of plasmatic level of gonadotropins and is the most frequent reason of hy- pogonadism in men. Although it is supposed that about 90 % of non-mosaic syndrome cases have fully azoospermia, it may be possible that some level of spermatogenesis are presented in seminiferous tubules in men with Klinefelter syndrome [48]. The mosaic XY, XXY/46, 47 have different levels of sperm production but the percentage of men which have sperm in semen is not clear. Such patients can be experience the preg- nancy with ICSI (Intracytoplasmic sperm injection). However, the risk of having a child with chromosomal malformation is high in this situation [49, 50].
Another source of aneuploidy is chromosomal translocation [51]. Translocations can lead to loss of genetic material in the breakage location of chromosome and hence, breakage of ge- netic message [52]. The autosomal translocation in sterile men is about 4 to 10 cm more than natural men [52, 53]. The Rob- ertsonian translocation which is happened in acrocentric chromosomes is the most frequent structural chromosomal malformation in human and affects the productivity of 1 in each 1000 men [54-61]. Although the prevalence of this type of translocation is only 0.8 % in sterile men, this number is 9 times more than natural population [62-65]. The translocations can lead to a spectrum of phenotypes in sperm production from the natural production of sperm to incapability in pro- duction of spermatogenesis [66].
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The Y chromosome is critically studied in the field of infertility due to having many of necessary genes for spermatogenesis and genesis of gonads [41]. Microdeletion in the Y chromo- some is one of the important factors in infertility of men. It is described as the deletion of chromosome which is included some genes but such deletion cannot be recognized by cus- tomary cytogenetic techniques [42]. The studies show that mi- crodeletion is usual in men with azoospermia and or severe oligozoospermia [43]. It is more happened in long arm of the chromosome (Yq) and the deletion in this region is accompa- nied by deficiency in spermatogenesis [44, 45]. The considered region is named as AZF (Azoospermia factor region) due to having some genes which are necessary for growing of sperm. The region is subdivided to three sections named as AZFa, AZFb and AZFc [46].
The most deficiencies in these sections are multi-genes dele- tions in AZFb and AZFc which can lead to a spectrum of infer- tility phenotypes [47]. Microdeletion is found in sections of AZF in azoospermia and oligozoospermia men with natural karyotype [48].
AZFa: two important genes in this section are USP9Y (Ubiquitin specific peptidase 9, Y-linke) and DBY. The dele- tions of both genes are led to Sertoli cell-only syndrome in which sertoli cells are complete in testicle but there are not any sperm in semen [49, 50].
In a research program for men subjected to sertoli-cell only syndrome it is shown that the description level of DBY is re- duced but other investigated genes are in natural level [51].
USP9Y also is critical in spermatogenesis and its deletion
can result to azoospermia, oligozoospermia and oligoastheno- zoospermia [52, 53].
AZFb: the deletion in this section is a key factor in stopping
of spermatogenesis in the first steps of spermatocyte which is clearly shows the importance of the gene in fertility [54]. The important gene of this section is RBMY which there are 6 cop- ies of the gene in the Y chromosome [55]. The gene codes an attaching protein to RNA which is a proprietary splicing factor in testicle and is explained in the core of spermatogenesis, spermatocyte and spermatid [56]. The description of this gene is reduced in azoospermia men [57]. There is also a family of PRY genes in AZFb. They are interfered in the regulation of programmed cell dead (apoptosis) which is a necessary pro- cess in deletion of unnatural sperms in the population of spermatozoa [58].
AZFc: the deletion in this section also leads to a wide spec- trum of phenotypes which most of them included reducing of sperms due to reduce in spermatogenesis [59]. The deletion in the section is responsible for 12 % of non-blockage azoo- spermia and 6 % of severe oligozoospermia cases [60]. AZFc is prone to many tiny deletions which are resulted due to intra chromosomal new composition [61]. Such deletions interact
with environmental factors and genetic potential which can be lead to a spectrum of phenotypes from natural production of sperm to azoospermia [62]. DAZ (Deleted in azoospermia) which has 4 copies of the Y chromosome has different roles in spermatogenesis and describes in all steps of growing of pro- lific cells [63].
CDY: the other important gene in spermatogenesis is CDY in Yq which codes a chromodomain protein. The gene is exclu- sively describes in testicle and make the replacement of his- tones in spermatogenesis easier. In addition, it allows easy access for proteins which regulate copies via histone acetyla- tion [64]. The gene has differently performed compared to its homologue autosoma (CDYL gene in chromosome 6) during evolution process and hence, it migrates to the Y chromosome. It is a considered gene since there is imply to a hypothesis that explained the genes which are interfered in spermatogenesis are tend to populate in the Y chromosome [65].
TSPY (Testis-specific protein Y): this gene is located on the short arm of the Y chromosome and has some copies on the long arm [66]. The gene is explained in testicle and its protein is interfered in spermatogenesis [67]. It seems that the gene characterize the time of spermatogenesis with sending a signal to the spermatogonia for entering of meiosis [68].
Many of autosomal genes can have a role in infertility of men. CFTR (Cystic fibrosis transmembrane conductance regulator) is presented in the chromosome 7 of 60 to 90 % of patients sub- jected to mutated congenital bilateral absence of the vas def- erens (CBAVD) [50-66]. CBAVD is a type of non-blockage azoospermia in which the lack of relation between Epididymis and Ejaculatory duct lead to infertility. Men subjected to CBAVD have mostly two soft mutations in CFTR and or a composition of severe mutation or soft mutation in the gene. The most frequent severe mutation is F508del which is found in 60-70 % of patients subjected to CBAVD [69].
SHBG (Sex hormone-binding globulin): this gene in chro- mosome 17 has been studied for possible role in spermatogen- esis. The role of its product is transmission of sexual hormones to the target location and control of androgens concentration in testicle [70]. Androgens have a critical role in sexual differ- entiating and spermatogenesis process. If the level of andro- gens experiences some disorder, it can be affect fertility. An investigation about the role of polymorphism n SHBG (TAAAA) in fertility of men concluded that shorter alleles of SHBG are along with increase in spermatogenesis levels. The shorter alleles of SHBG with increase in level of SHBG lead to increase in level of free androgens and hence, incitement of spermatogenesis [71].
ESR1 (Estrogen receptor) and ESR2: the studies about the relation of unnatural spermatogenesis and insufficient estro- gens led to more studies about the estrogen receptor genes [72]. ESR1 in chromosome 6 has high polymorphism which their role in infertility, especially about severe oligozoospermi,
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has been studied and the results have been different [73]. The differences may be due to interaction of gene with environ- ment since the differences are mostly between various de- scents.
FSHR (Follicle-stimulating hormone receptor): this gene is located on the chromosome 2 and codes the receptor of FSH hormone (necessary hormone for natural activity of gonads). It is shown in a study that the relative deletion of this gene leads to ignorable effects on spermatogenesis [74]. In addition, it is found that the single nucleotide polymorphism affect the ac- tivity of gene [75].
MTHFR (Methylenetetrahydrofolate reductase): this gene is located on the short arm of chromosome 1 and codes an en- zyme which interfered in folate metabolism and has an im- portant role in DNA methylation and spermatogenesis process [76]. Polymorphism of 677C T is the reason of replacing ala- nine to valine which reduces the activity of enzyme [77]. Re- duction of activity in MTHFR leads to mis-regulation of folate metabolism and hence, inaccuracy in methylation of DNA and some effects on spermatogenesis [78]. This polymorphism is related to infertility of African, South East Asian and Indian men [79, 80] but such results are not validated for European population [81].
Numerous genes located in the X chromosome are explained in testicle and hence, have role in gametogenesis [81]. The an- drogen receptor (AR) is located on the long arm of X and is interfered in meiosis and conversion of spermatocyte to sper- matide in spermatogenesis process [82]. In a study on the ster- ile men, it was recognized that about 2 % of them have muta- tion in AR while such mutation was not seen in testimonial group [83].
USP26: it is located on the long arm of the X chromosome and is explained during the elementary steps of spermatogen- esis in testicle [84]. It seems that this gene has a role in histonic deletion process in spermatogenesis [85]. The previous results have been shown that there is a relationship between this gene and infertility, such as discovering of gene variants in azoo- spermia men [84].
KS (Kallmann syndrome): one of the other genetic diseases which is the reason of infertility in men and have both portion of autosomal and related to X. The syndrome is defined as IHH (Idiopathic hypogonadotropic hypogonadism) along with anosmia. IHH with low levels of sexual steroids is recog- nized in composition with low to natural levels of FSH and LH hormones [83]. Patients can be subjected to a spectrum of IHH from complete to incomplete which leads to a spectrum of sexual growing malformations [82]. The genetic deletions of FGFR1 (Fibroblast growth factor receptor) and KAL1 are relat- ed to the syndrome [81]. KAL1 is located on the short arm of the X chromosome and is interfered in migration of neurons of Gonadotropin-releasing hormones (GnRH) and codes Anos- min-1 protein which is a cohesion cell molecule [80]. The dele- tion of this gene is seen in 30 to 70 % of KS patients. The dele- tion of FGFR1 also results anosmia types in KS patients.
Spermatogenesis is a complex process which is resulted from a set of events, each of them are prone to mutations which can affect the process [79]. In addition, sperm shall be accu- rately categorized to transmission of genetic and epigenetic information to accurate growth of embryo. Epigenetic infor- mation means the changes of genetic codes which not affect DNA sequence; such as adding different molecules to DNA structure which changed the copy regulation and hence, gene explanation [78]. The chromatin packing is a critical case for genesis of sperm and it is believed that the com- pressed structure of chromatin transmitted urgent messages for genesis of embryo [76]. During the chromatin packing, 85
% of histones replace by protamines [74, 75].
In mid steps of this replacement, transitional protein en- tered to the chromatin structure [73]. The studies in mouse are shown that the destruction of genes that codes these pro- teins (TP1 and TP2) can lead to infertility phenotype [71, 72]. In addition, the performances of two different proteins of protamine P1 and P2 are recognized in human so that if mRNA related to P1 explained very soon, the spermatogene- sis stopped in spermatide step [70]. Histones are another im- portant factor in epigenetic transmission and they are high- lighted imprinting control regions during the production of spermatogenesis. Explanation regulation control of genes is performed by adding acetyl, methyl, ubiquitin and phos- phate to histones [69]. The histone malformation is a poten- tial candidate for germinal malformation and their roles in infertility are still under investigation [68].
Imprinting of DNA methylation determined what gene is explained by father or mother genome. The imprinted re- gions in DNA are repeatedly imprinting during each sexual cycle and allow stabilizing the parental imprints in cells with prolific level [67]. Kobayashi et al. studied the validity of im- printing in sterile men. In prolific men with natural ejacula- tion, differentiated regions of father should be methylated while mother regions should be un-methylated. The study showed that about 14 % of sterile men have malformation in differentiated regions of father and 21 % of sterile men have malformation in differentiated regions of mother. Most of patients having malformation in both regions are oligozoo- spermia. In addition, assisted reproductive techniques (ART) are of low rate of success in men with imprinted DMRs mal- formation. Moreover, it is found that oligozoospermia men are highly subjected to risk of transmission of imprint mis- takes to their children [66]. Telomere can be a potential can- didate in outbreak of infer tility phenotype. Telomere pro- tects the genetic information in chromosomes and localizes the chromosome in the core and plays a role in simulating of DNA [65]. Unnatural shortening of telomere is related to infertility in men [64]. Hemann et al. studied about the length of telomere in knock out mouse and found that there is a mechanism in telomerase enzyme which lead to de- struction of spermatocytes in short telomeres and hence, prevent from maturity of them [63]. However, the mecha- nism is not perfect. Liu et al. shown the spermatocytes that are able to path from control regions and reach to meiosis 1
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without any failure whiles the telomere is short [62]. At the other hand, study about the length of telomere in different infertility phenotypes including blockage and non-blockage azoospermia and oligozoospermia patients have not shown a clear difference in activity of telomerase [61]. As a result, the effect of telomere length shall be more studied as a productivity factor.
A field of genetic research about the infertility which is not interested for researchers until recent years is the role of mito- chondrion and its genome in infertility. Mitochondrion has an important role in all biochemical paths which one of them is the motility of sperm [60]. Motility of sperm is strongly related to production of ATP by mitochondrion. This case is per- formed by oxidative phosphorylation. During recent years, there found some mutations in mitochondrion genome which are related to some diseases. Most of mitochondrion muta- tions lead to special type of nervous - muscular and nervous analysis diseases.
Since the motility of sperm is needed to high amount of ATP to move the flagellin system, deficiency in respiratory chain of mitochondrion can lead to stagnancy of sperm and hence, in- fertility. About 70-80 % of mitochondrion is presented in mid section of sperm in mammals. Each mitochondrion has a copy of mitochondrion’s genome [59]. Since the bioangetic perfor- mance of sperm is critical for motility, any quantitative or qualitative deviation affects the cell performance of sperm. Firstly, infertility due to asthenozoospermia and oligoastheno- zoospermia (no to low sperm motility cases) in patients with mitochondrion malformations resulted from point mutation and deletion reported in some studies [58]. Secondly, it was shown that sperm is prone to deletion mutations in mtDNA and these mutations are related to decrease in motility of sperm. Thirdly, there found a relationship between respiratory chain performance in mitochondrion sperm and semen quali- ty. In addition, it found that point mutations and single nucle- otide polymorphism are effective in semen quality.
Use of assisted reproductive techniques such as ICSI may be transmitted the mitochondrion malformation to the child since sperm is completely inseminated to the ovocyte but other studies explained anomalous information which complicates the role of mitochondrion DNA in infertility of men. March- ington et al. reported that mitochondrion DNA of father in child produced by ICSI is not recognizable [57]. This finding confirms the hypothesis of breakup of mitochondrion DNA of father after zygosis [56].
miRNA are members of small not codeable RNA (mostly be- tween 19 to 23 nucleotides) which have a critical role in regu- lation of explanation after translation and silence of gene ex- planation via constitution of open pair with target mRNA [55]. Numerous miRNAs are explained in testicle of mouse, exclu- sively or preferentially, which is representative of their im- portant role in spermatogenesis [54]. The role of miRNA in anchoring of translation during spermatogenesis is suggested
with aggregation of biogenic paths of miRNA in chromatid bodies [52, 53]. It was found that transition protein 2 which is an exclusive gene of testicle is regulated via miR-122a [51]. In addition, in testicles that dicer deleted spermatogenesis is postponed during reproduction and or differentiation steps [50]. In a testimonial case study, Lian et al. compared the pro- file of miRNA in sound men and sterile men with semen mal- formation using microarray technique. Totally, explanation of
52 miRNA differed in two groups of sterile and sound men. The results confirmed by qRTPCR (quantitative real-time pol- ymerase chain reaction) and northern blot and it found that miR-574-5p, miR-297, miR-122, miR-1275, miR-373, miR-185 and miR-193b are of increase in explanation and miR-100, miR-512-3p, miR-16, miR-19b, miR-23b and miR-26a are of decrease in explanation in semen of sterile men [49]. More studies in this field can lead to finding new cases and role of miRNA in infertility.
DPY19L2: during an international cooperation, one the effec- tive genes in infertility of men discovered. This gene is named as DPY19L2 and is related to a case named as round headed sperm or globozoospermia which is a factor of infertility in low percent of sterile men (lower than 1 % of sterile men). This situation is explained by presence of 100 % of non chromo- some sperms in semen analysis via optical microscope. In this study that performed in a Jordanian family, 5 brothers recog- nized as fully globozoospermia which 4 of them are of hemozygote deletion 200 kb in chromosome 12. This region is only consists of DPY19L2. Similar deletions in non-related patients is showed that delete of this gene is one of the im- portant factors of globozoospermia and hence, infertility in men [48].
GLUT3 and CASPR5: in 2012, researchers of Baylor medical college in Texas recognized the factor of infertility in a group of sterile men. They studied DNA genome of environmental blood for 22 men with non-blockage azoospermia and 4 re- productive men using array CGH technique to compare the copy number variation. The added and missed copies recog- nized and candidate genes selected. After supplementary tests, it found that among 22 sterile patients, 2 of them are of extra copy number in GLUT3 and one of them is of extra copy number in CASPR5. The supplementary investigation on more
43 sterile men showed that there are extra copy number in GLUT3 of 5 patients and missed copy number in CASPR5 of one patient. The frequency of copy number variation in GLUT3 and CASPR5 in general population of reproductive and sterile men are about 5 and 0.002 %, respectively, while in this study they are about 16 and 4 %, respectively [47]. It should be noted that GLUT3 is a protein which cause to transmission of glucose from plasmatic membrane in mam- mals. This is named as neuron transporter due to its exclusive role in neuron cells. The role of GLUT3 in cells which have need to glucose, such as sperm also studied. The production of CASPR5 is belonged to neuroxin family which some of its members act as cohesion cell molecules and receptor in nerv- ous system of vertebrates.
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Mutation in NR5A1: in cooperation between Pastor Insti- tute of Paris and children health institute of London in a study of 315 men, it found that mutation in NR5A1 can be an unex- plained factor of infertility in men. This gene codes a protein that is of an important role in genesis of sexual organ [46].
SRPK: the researchers of Edinburgh University with study of hundreds of sterile vinegar houseflies shown that the lack of SRPK performance can be lead to chromosomal un- aggregation and hence, infertility and decrease in level of productivity. This phenomenon is also seen in mammals and human cells [45].
With continuing progress of different aspects of life sciences, researchers are able to understand the interactions of genetic, environmental and descent factors in infertility. Although there are still many works to accurately complete the effective genetic factors in infertility, recent studies are signified the need to accurate transmission of epigenetic information along with genetic factors to correct pregnancy. More studies in ne- glected fields of infertility such as mitochondrion genetics and miRNA may be caused to finding other regulatory factors in the gametogenesis process. Using the whole of these infor- mation, clinics will be more capable to infertility remediation and they will be able to make better decision in use of assisted reproductive tools.
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