The Male Is Significantly Implicated as the Cause of Unexplained Infertility

2020 ◽  
Vol 38 (01) ◽  
pp. 003-020
Author(s):  
Robert John Aitken
Keyword(s):  
Oxidative Stress ◽  
Male Infertility ◽  
De Novo ◽  
Deep Understanding ◽  
Epigenetic Factors ◽  
De Novo Mutations ◽  
Male Factor ◽  
Male Germline ◽  
Broad Array ◽  
Ejaculation Frequency

AbstractMale infertility is recognized as a relatively common, complex condition, generated by a broad array of environmental and genetic factors. Historical reliance on the conventional semen profile has tended to underestimate the true contribution of “the male factor” to human infertility. This review highlights the importance of genetic and epigenetic factors in the etiology of male infertility, identifying a range of mutations responsible for primary testicular failure and impaired fertilizing potential. More than three quarters of all de novo mutations arise in the male germline via mechanisms that involve the inefficient or defective repair of DNA damage. Understanding the range of factors capable of creating genetic turmoil in the paternal germline is essential, if we are to gain a deep understanding of the causes of male infertility, rather than just the symptoms that characterize its presence. High levels of DNA fragmentation induced by oxidative stress are part of this equation. Oxidative stress is, in turn, driven by biological (age, ejaculation frequency, varicocele, infection), lifestyle (smoking, obesity), and environmental factors (heat, other forms of electromagnetic radiation, and toxins) that can impair the fertilizing potential of the spermatozoa and influence the incidence of spontaneous mutations that may cause infertility in the offspring.

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
MS Oud ◽  
RM Smits ◽  
HE Smith ◽  
FK Mastrorosa ◽  
GS Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

IntroductionDe novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness1. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00×10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01×10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing2. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

scholarly journals Epigenetic reprogramming during spermatogenesis and male factor infertility

Reproduction ◽  
2018 ◽  
Vol 156 (2) ◽  
pp. R9-R21 ◽  
Author(s):  
H M McSwiggin ◽  
A M O’Doherty
Keyword(s):  
Dna Methylation ◽  
Male Infertility ◽  
Deep Sequencing ◽  
Male Factor Infertility ◽  
Male Factor ◽  
Chromatin Dynamics ◽  
Sequencing Technologies ◽  
Male Germline ◽  
Male Factors ◽  
Epigenetic Processes

Infertility is an often devastating diagnosis encountered by around one in six couples who are trying to conceive. Moving away from the long-held belief that infertility is primarily a female issue, it is now recognised that half, if not more, of these cases may be due to male factors. Recent evidence has suggested that epigenetic abnormalities in chromatin dynamics, DNA methylation or sperm-borne RNAs may contribute to male infertility. In light of advances in deep sequencing technologies, researchers have been able to increase the coverage and depth of sequencing results, which in turn has allowed more comprehensive analyses of spermatozoa chromatin dynamics and methylomes and enabled the discovery of new subsets of sperm RNAs. This review examines the most current literature related to epigenetic processes in the male germline and the associations of aberrant modifications with fertility and development.

scholarly journals Iron overload is accompanied by mitochondrial and lysosomal dysfunction in WDR45 mutant cells

Brain ◽  
2018 ◽  
Vol 141 (10) ◽  
pp. 3052-3064 ◽  
Author(s):  
Philip Seibler ◽  
Lena F Burbulla ◽  
Marija Dulovic ◽  
Simone Zittel ◽  
Johanne Heine ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
De Novo ◽  
Induced Pluripotent Stem Cell ◽  
Patient Specific ◽  
Autophagic Flux ◽  
De Novo Mutations ◽  
Animal Cells ◽  
Mutant Cells

Abstract Beta-propeller protein-associated neurodegeneration is a subtype of monogenic neurodegeneration with brain iron accumulation caused by de novo mutations in WDR45. The WDR45 protein functions as a beta-propeller scaffold and plays a putative role in autophagy through its interaction with phospholipids and autophagy-related proteins. Loss of WDR45 function due to disease-causing mutations has been linked to defects in autophagic flux in patient and animal cells. However, the role of WDR45 in iron homeostasis remains elusive. Here we studied patient-specific WDR45 mutant fibroblasts and induced pluripotent stem cell-derived midbrain neurons. Our data demonstrated that loss of WDR45 increased cellular iron levels and oxidative stress, accompanied by mitochondrial abnormalities, autophagic defects, and diminished lysosomal function. Restoring WDR45 levels partially rescued oxidative stress and the susceptibility to iron treatment, and activation of autophagy reduced the observed iron overload in WDR45 mutant cells. Our data suggest that iron-containing macromolecules and organelles cannot effectively be degraded through the lysosomal pathway due to loss of WDR45 function.

De novo mutations in idiopathic male infertility ‐ a pilot study

Andrology ◽  
2020 ◽  
Author(s):  
A. Hodžić ◽  
A. Maver ◽  
D. Plaseska‐Karanfilska ◽  
M. Ristanović ◽  
P. Noveski ◽  
...  
Keyword(s):  
Pilot Study ◽  
Male Infertility ◽  
De Novo ◽  
De Novo Mutations ◽  
Idiopathic Male Infertility

scholarly journals Oxidative Stress in the Male Germline: A Review of Novel Strategies to Reduce 4-Hydroxynonenal Production

Antioxidants ◽  
2018 ◽  
Vol 7 (10) ◽  
pp. 132 ◽  
Author(s):  
Jessica Walters ◽  
Geoffry De Iuliis ◽  
Brett Nixon ◽  
Elizabeth Bromfield
Keyword(s):  
Oxidative Stress ◽  
Germ Cells ◽  
Cell Function ◽  
De Novo ◽  
Protein Translation ◽  
Egg Recognition ◽  
Male Germline ◽  
New Strategy ◽  
Artery Disease ◽  
The Stability

Germline oxidative stress is intimately linked to several reproductive pathologies including a failure of sperm-egg recognition. The lipid aldehyde 4-hydroxynonenal (4HNE) is particularly damaging to the process of sperm-egg recognition as it compromises the function and the stability of several germline proteins. Considering mature spermatozoa do not have the capacity for de novo protein translation, 4HNE modification of proteins in the mature gametes has uniquely severe consequences for protein homeostasis, cell function and cell survival. In somatic cells, 4HNE overproduction has been attributed to the action of lipoxygenase enzymes that facilitate the oxygenation and degradation of ω-6 polyunsaturated fatty acids (PUFAs). Accordingly, the arachidonate 15-lipoxygenase (ALOX15) enzyme has been intrinsically linked with 4HNE production, and resultant pathophysiology in various complex conditions such as coronary artery disease and multiple sclerosis. While ALOX15 has not been well characterized in germ cells, we postulate that ALOX15 inhibition may pose a new strategy to prevent 4HNE-induced protein modifications in the male germline. In this light, this review focuses on (i) 4HNE-induced protein damage in the male germline and its implications for fertility; and (ii) new methods for the prevention of lipid peroxidation in germ cells.

scholarly journals A de novo paradigm for male infertility

2021 ◽  
Author(s):  
Joris Veltman ◽  
Manon Oud ◽  
Roos Smits ◽  
Hannah Smith ◽  
Francesco Mastrorosa ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
P Value ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment

Abstract De novo mutations (DNMs) are known to play a prominent role in many sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. We performed a trio-based exome-sequencing study in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

scholarly journals A de novo paradigm for male infertility

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
M. S. Oud ◽  
R. M. Smits ◽  
H. E. Smith ◽  
F. K. Mastrorosa ◽  
G. S. Holt ◽  
...  
Keyword(s):  
Male Infertility ◽  
De Novo ◽  
Missense Mutations ◽  
Loss Of Function ◽  
De Novo Mutations ◽  
Systematic Analysis ◽  
Significant Enrichment ◽  
Infertile Patients

AbstractDe novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

scholarly journals Male Infertility: Shining a Light on Lipids and Lipid-Modulating Enzymes in the Male Germline

2020 ◽  
Vol 9 (2) ◽  
pp. 327 ◽  
Author(s):  
Jessica L.H. Walters ◽  
Bart M. Gadella ◽  
Jessie M. Sutherland ◽  
Brett Nixon ◽  
Elizabeth G. Bromfield
Keyword(s):  
Male Infertility ◽  
Assisted Reproductive Technologies ◽  
Membrane Lipids ◽  
Treatment Options ◽  
Reproductive Technologies ◽  
Male Factor ◽  
Male Germline ◽  
Efficacious Treatment ◽  
Cellular Dysfunction ◽  
The Impact

Despite the prevalence of male factor infertility, most cases are defined as idiopathic, thus limiting treatment options and driving increased rates of recourse to assisted reproductive technologies (ARTs). Regrettably, our current armory of ARTs does not constitute therapeutic treatments for male infertility, thus highlighting an urgent need for novel intervention strategies. In our attempts to fill this void, we have come to appreciate that the production of pathological levels of oxygen radicals within the male germline are a defining etiology of many idiopathic infertility cases. Indeed, an imbalance of reactive oxygen species can precipitate a cascade of deleterious sequelae, beginning with the peroxidation of membrane lipids and culminating in cellular dysfunction and death. Here, we shine light on the importance of lipid homeostasis, and the impact of lipid stress in the demise of the male germ cell. We also seek to highlight the utility of emerging lipidomic technologies to enhance our understanding of the diverse roles that lipids play in sperm function, and to identify biomarkers capable of tracking infertility in patient cohorts. Such information should improve our fundamental understanding of the mechanistic causes of male infertility and find application in the development of efficacious treatment options.

scholarly journals Discovery of an unusual high number of de novo mutations in sperm of older men using duplex sequencing

2021 ◽  
Author(s):  
Renato Salazar ◽  
Barbara Arbeithuber ◽  
Maja Ivankovic ◽  
Monika Heinzl ◽  
Sofia Moura ◽  
...  
Keyword(s):  
De Novo ◽  
Age Groups ◽  
Low Frequency ◽  
Congenital Disorders ◽  
Sequence Information ◽  
De Novo Mutations ◽  
Coding Region ◽  
Male Germline ◽  
Significant Difference ◽  
Duplex Sequencing

AbstractDe novo mutations (DNMs) are an important player in heritable diseases and evolution, yet little is known about the different mutagenic processes in our germline given the difficulty to reliably identify ultra-low frequency variants. Of particular interest are highly recurrent DNMs associated with congenital disorders that have been described as selfish mutations expanding in the male germline, thus becoming more frequent with age. Here, we have adapted duplex sequencing (DS), an ultra-deep sequencing method that renders sequence information on both DNA strands; thus, one mutation can be reliably called in millions of sequenced bases. With DS, we examined ~4.5 kb of the FGFR3 coding region in sperm DNA from older and younger donors. We identified highly mutable sites with mutation frequencies 4-5 orders of magnitude higher than the genome average. Multiple mutations were found at a higher frequency, or exclusively, in older donors, suggesting that these mutations are testis exclusive mosaics expanding in the male germline with age. Also, older donors harbored more mutations associated with congenital disorders. Some mutations were found in both age groups with no significant difference, suggesting that these might result from a different mechanism (e.g., post-zygotic mosaicism). We also observed that independently of age, the frequency and deleteriousness of the mutations in sperm were elevated compared to reports in the population. Our approach is an important strategy to identify mutations that could be associated with aberrant receptor tyrosine kinase activity, with unexplored consequences in a society with delayed fatherhood.

scholarly journals The Impact of Oxidative Stress in Male Infertility

2022 ◽  
Vol 8 ◽  
Author(s):  
Amanda Mannucci ◽  
Flavia Rita Argento ◽  
Eleonora Fini ◽  
Maria Elisabetta Coccia ◽  
Niccolò Taddei ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Male Infertility ◽  
Causative Factor ◽  
Ros Production ◽  
Clinical Use ◽  
Oxygen Species ◽  
Male Factor ◽  
Stress Assessment ◽  
The Impact

At present infertility is affecting about 15% of couples and male factor is responsible for almost 50% of infertility cases. Oxidative stress, due to enhanced Reactive Oxygen Species (ROS) production and/or decreased antioxidants, has been repeatedly suggested as a new emerging causative factor of this condition. However, the central roles exerted by ROS in sperm physiology cannot be neglected. On these bases, the present review is focused on illustrating both the role of ROS in male infertility and their main sources of production. Oxidative stress assessment, the clinical use of redox biomarkers and the treatment of oxidative stress-related male infertility are also discussed.

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