Genetic Origin of Male Infertility – Y Chromosome Microdeletions and its Effect on Spermatogenesis. A Review of Literature
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Date
2020
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Rīgas Stradiņa universitāte
Rīga Stradiņš University
Rīga Stradiņš University
Abstract
Par reproduktīvo sistēmu atbildīgo gēnu izmaiņas ir fonā vīriešu neauglības attīstībai; tādējādi ietekmē dažādus fizioloģiskos procesus, tostarp hormonālo homeostāzi, spermatoģenēzi un spermatozoīdu kvalitāti. Tāpēc, lai pienācīgi pārvaldītu neauglīgu pāri, izšķiroša nozīme ir dziļai reproduktīvās mazspējas ģenētiskā pamata izpratnei. Tiek uzskatīts, ka vīriešu neauglība ir viens no visvairāk mulsinošajiem traucējumiem reproduktīvajā jomā, un tā izplatība pieaug, kamēr tā etioloģija joprojām ir noslēpumaina. Pēc Klinefeltera sindroma [47, XXY] Y-hromosomu mikrodelēcijas ir otrais galvenais vīriešu neauglības ģenētiskais cēlonis. Mikrodelēcijas Y-hromosomā, kas saistītas ar neauglību, rodas garās rokas [Yq11] atsevišķos apgabalos, kurus dēvē par azoospermijas faktora [AZF] reģionu. Mikrodelēcijas var izraisīt nopietnus spermas ražošanas un funkciju traucējumus, kas noved pie dažādas pakāpes disoospermijas, sākot no oligozoospermijas [samazināta spermas ražošana] līdz azoospermijai [spermas trūkums ejakulātā] neauglīgiem vīriešiem. Līdz šim lielākā daļa autoru ir vienisprātis, ka ar neauglību saistītas Y-hromosomas mikrodelēcijas rodas AZF apakšreģionos Yq un tie ir viens no visizplatītākajiem smagas oligo- / azoospermijas ģenētiskajiem cēloņiem. Lielākā daļa un visbiežāk svītrojumi notiek AZFc, kam seko AZFa [b2/b4], AZFb [P5/proksimālais P1] un visbeidzot AZFbc [P5 / distālais P1 un P4 /distālais P1]. Daudzi autori ir panākuši vienprātību par šo svītrojumu rašanās mehānismu un seku sekām vīriešiem. Mikrodelēcijas rodas homologas rekombinācijas dēļ starp amplikoniskajām sekvencēm palindromos. Molekulāro metožu ieviešana ir devusi milzīgu ieskatu vīriešu neauglības ģenētiskajā izcelsmē, tomēr pētījumi joprojām nespēj noteikt precīzu cēloņu-seku saistību un genotipa-fenotipa korelāciju starp atsevišķām Y-hromosomu mikrodelēcijām un dažādiem, ļoti neparedzamiem spermatogēnie modeļi, kas novēroti neauglīgiem vīriešiem. Y-hromosomu mikrodelēciju biežums literatūrā joprojām ir apstrīdams. Ģenētiskā pārbaude, molekulārā diagnostika un konsultēšana ir kritiski svarīgi, un tie jāpiedāvā pāriem, pirms tiek apsvērtas tādas procedūras kā intracitoplazmatiska spermas injekcija [ICSI] un in vitro apaugļošana [IVF], jo šīs vīrieša mikrodelēcijas un spermatogēnie defekti tiek pārnesti uz viņa tēviņu pēcnācējiem. ja reproduktīvās tehnoloģijas tehnoloģija [ART], izmantojot viņa spermu, ir veiksmīga. Šajā visaptverošajā literatūras apskatā tiks mēģināts plaši apspriest Y-hromosomu mikrodelēcijas, šo Y-hromosomu svītrojumu biežumu visā pasaulē un tā ietekmi uz vīriešu neauglību, raksturojot AZF svītrojumus, genotipa-fenotipa korelācijas, spermatoģenēzes izmaiņas un arī pamatojot ģenētiskās konsultācijas ir obligāta, pirms tiek veiktas jebkādas mākslīgās apaugļošanas procedūras.
Alterations in genes responsible for the reproductive system is in the background for the development of male infertility; consequently affecting various physiological processes including hormonal homeostasis, spermatogenesis, and spermatozoa quality. Hence why a deep understanding of the genetic basis of reproductive failure is crucial to appropriately manage an infertile couple. Believed to be one of the most confounding disorders in the reproductive field, male factor infertility is ubiquitous, and its prevalence is increasing while its aetiology remains mysterious. Following Klinefelter syndrome [47, XXY], Y-chromosomal microdeletions are the second leading genetic cause of male infertility. Microdeletions in the Y-chromosome linked with infertility arise in distinct areas of the long arm [Yq11] called the azoospermia factor [AZF] region. Microdeletions can result in severe impairment of sperm production and function that lead to varying degrees of dyszoospermia, from oligozoospermia [reduced sperm production] to azoospermia [lack of sperm in the ejaculate] in infertile men. To date, most authors agree that microdeletions in the Y-chromosome connected to infertility arise in the AZF subregions on Yq and they are one of the most common genetic cause of severe oligo-/azoospermia. The vast majority and most frequent deletions occur in the AZFc, followed by the AZFa [b2/b4], AZFb [P5/proximal P1] and lastly the AZFbc [P5/distal P1 and P4/distal P1]. Many authors have reached a consensus as to the mechanism of how these deletions happen and the consequential outcomes of these deletions in men. Microdeletions occur because of homologous recombination between ampliconic sequences in palindromes. The introduction of molecular techniques has granted an immense insight into the genetic origin of male infertility, however, research studies are still unable to determine the precise cause-effect relationship and genotype-phenotype correlation between certain Y-chromosome microdeletions and the various, extremely unpredictable spermatogenic patterns observed in infertile men. Alas, the worldwide frequency of Y-chromosome microdeletions in literature remains debatable. Genetic testing, molecular diagnosis and counselling are critical and should be offered to couples before procedures such as intracytoplasmic sperm injection[ICSI] and in-vitro fertilization [IVF] are considered because these microdeletions and spermatogenic defects in a man are transmitted to his male offspring if the assisted reproductive technology [ART] using his sperm is successful. This comprehensive review of literature will endeavour to extensively discuss Y-chromosome microdeletions, the worldwide frequency of these Y-chromosomal deletions and its effect on male infertility by characterizing AZF deletions, genotype-phenotype correlations, alterations of spermatogenesis and to also justify why genetic counselling is mandatory before any assisted reproduction procedures are conducted.
Alterations in genes responsible for the reproductive system is in the background for the development of male infertility; consequently affecting various physiological processes including hormonal homeostasis, spermatogenesis, and spermatozoa quality. Hence why a deep understanding of the genetic basis of reproductive failure is crucial to appropriately manage an infertile couple. Believed to be one of the most confounding disorders in the reproductive field, male factor infertility is ubiquitous, and its prevalence is increasing while its aetiology remains mysterious. Following Klinefelter syndrome [47, XXY], Y-chromosomal microdeletions are the second leading genetic cause of male infertility. Microdeletions in the Y-chromosome linked with infertility arise in distinct areas of the long arm [Yq11] called the azoospermia factor [AZF] region. Microdeletions can result in severe impairment of sperm production and function that lead to varying degrees of dyszoospermia, from oligozoospermia [reduced sperm production] to azoospermia [lack of sperm in the ejaculate] in infertile men. To date, most authors agree that microdeletions in the Y-chromosome connected to infertility arise in the AZF subregions on Yq and they are one of the most common genetic cause of severe oligo-/azoospermia. The vast majority and most frequent deletions occur in the AZFc, followed by the AZFa [b2/b4], AZFb [P5/proximal P1] and lastly the AZFbc [P5/distal P1 and P4/distal P1]. Many authors have reached a consensus as to the mechanism of how these deletions happen and the consequential outcomes of these deletions in men. Microdeletions occur because of homologous recombination between ampliconic sequences in palindromes. The introduction of molecular techniques has granted an immense insight into the genetic origin of male infertility, however, research studies are still unable to determine the precise cause-effect relationship and genotype-phenotype correlation between certain Y-chromosome microdeletions and the various, extremely unpredictable spermatogenic patterns observed in infertile men. Alas, the worldwide frequency of Y-chromosome microdeletions in literature remains debatable. Genetic testing, molecular diagnosis and counselling are critical and should be offered to couples before procedures such as intracytoplasmic sperm injection[ICSI] and in-vitro fertilization [IVF] are considered because these microdeletions and spermatogenic defects in a man are transmitted to his male offspring if the assisted reproductive technology [ART] using his sperm is successful. This comprehensive review of literature will endeavour to extensively discuss Y-chromosome microdeletions, the worldwide frequency of these Y-chromosomal deletions and its effect on male infertility by characterizing AZF deletions, genotype-phenotype correlations, alterations of spermatogenesis and to also justify why genetic counselling is mandatory before any assisted reproduction procedures are conducted.
Description
Medicīna
Medicine
Veselības aprūpe
Health Care
Medicine
Veselības aprūpe
Health Care
Keywords
Y hromosomas mikrodelēcijas, vīriešu neauglības, ģenētiskais iemesls, biežums skrīninga un diagnostikas metodes un spermatoģenēzi, Y-chromosome microdeletion, male infertility, genetic origin, incidence, screening and diagnostic methods and spermatogenesis