Effect and in silico characterization of genetic variants associated with severe spermatogenic disorders in a large Iberian cohort

Abstract

YAO et Al. | INTRODUC TI ONSince the first case of coronavirus disease 2019 , caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was reported in Wuhan, China, it has rapidly spread and affected more than 21 million people worldwide as of 17 August 2020. 1 SARS-CoV-2 uses angiotensin-converting enzyme II (ACE2) to enter host cells, similar to SARS-CoV, which emerged 18 years ago. 2 COVID-19 induces respiratory-predominant multiorgan dysfunction, including myocardial, renal, enteric and hepatic dysfunction, which coincides with the tissue expression of ACE2. 3 Meanwhile, several studies have shown that ACE2 is expressed in human testes (eg spermatogonia, Leydig cells and Sertoli cells), 4,5 suggesting that the testes may be another organ affected by COVID-19.Numerous viruses have been detected in human semen. 6 Viruses may persist in semen and last longer in seminal fluid than in other body fluids due to the immune privilege of the testes and the contribution of the blood-testes barrier to resistance to therapeutic agents. 7,8 Semen may also have higher loads of viruses, such as Zika virus, than blood. 9,10 Therefore, the testes may act as a reservoir of virus, which may cause imprecise evaluation of viral clearance in patients. Viruses, including Zika virus, Ebola virus, cytomegalovirus and human immunodeficiency virus (HIV), have been isolated from semen and can be sexually transmitted. 6,11,12 Furthermore, some viruses (eg HIV, Zika virus, herpes simplex virus (HSV) and human papillomavirus) can adhere to or be internalized by spermatozoa, 7,13 which may pose a risk for embryonic infection and cause adverse reproductive outcomes.On the other hand, many viruses, such as mumps virus, HIV and HSV, 7,14 have been found to impair semen quality, and they may directly interact with spermatozoa or affect spermatogenesis by inducing local inflammation. [15][16][17] Previous studies found that SARS, 1 of the 3 epidemic coronaviruses to emerge in the past 20 years and that shows similar clinical presentations to COVID-19, 18 could cause orchitis 19 and focal testicular atrophy. 20 Considering the tens of millions of COVID-19 cases and that men are more vulnerable to COVID-19 than women, [21][22][23] it is imperative to determine the effect of COVID-19 on male reproduction. 24 Several studies have been performed on this topic. However, the results are controversial. For example, some researchers have reported that SARS-CoV-2 was not detected in the male reproductive tract, [25][26][27][28][29][30][31][32][33][34] while others reported that SARS-CoV-2 RNA was found in the semen or testes of COVID-19 patients. 35,36 There are also unknown factors regarding COVID-19 and male reproduction.Orchitis and broad destruction of the testes were found in deceased COVID-19 patients, 35,37 while the pathological characteristics in survivors remain unknown. In this review, we summarize the current research focusing on the effects of COVID-19 on male reproduction from the following 3 aspects: detection of SARS-CoV-2 in...

The Role of Long Noncoding RNAs on Male Infertility: A Systematic Review and In Silico Analysis

“…One more article was also excluded, as it was a perspective and did not present original data. Finally, a total of 20 articles remained to be included in the present systematic review [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ].…”

Common Variation in the PIN1 Locus Increases the Genetic Risk to Suffer from Sertoli Cell-Only Syndrome

“…The analysis of common variants located in potentially relevant genes for spermatogenesis is crucial for unraveling the genetic component underlying the male infertility phenotypes with idiopathic molecular etiology [ 13 ]. Frequent mutant alleles are known to modify or disrupt gene expression subtly and, in specific contexts or if certain environmental factors are present, they might alter the correct production of male gametes [ 36 , 37 ]. Therefore, the reported findings should not be interpreted as highly damaging and rare mutations causing infertility, but in the context of the identification of genetic markers for a complex disease [ 13 ].…”

Common genetic variation in KATNAL1 non‐coding regions is involved in the susceptibility to severe phenotypes of male infertility

“…Thus, NOA patients were classified further into the following major subgroups according to the histological analysis: (1) Sertoli‐cell only syndrome group (SCO, if a total absence of germ cells was observed), (2) maturation arrest of germ cells group (MA, patients with > 90% of maturation arrest of the germ line either at the spermatogonia or primary spermatocyte stages) and (3) hypospermatogenesis group (HS, including patients with extremely low cellularity but with all cell types of the germ line present in few testicular locations). Additionally, we also established two additional subgroups based on the TESE outcome of NOA patients, that is, TESEneg (if no viable sperm cell was retrieved from the biopsy) and TESEpos (including NOA patients with a successful sperm retrieval), as detailed elsewhere 20 . All the available information regarding the main clinical features of our study cohort is shown in Table S1.…”

“…Additionally, we also established two additional subgroups based on the TESE outcome of NOA patients, that is, TESEneg (if no viable sperm cell was retrieved from the biopsy) and TESEpos (including NOA patients with a successful sperm retrieval), as detailed elsewhere. 20 All the available information regarding the main clinical features of our study cohort is shown in Table S1.…”