Genetics of teratozoospermia: Back to the head

Beurois, Julie; Cazin, Caroline; Kherraf, Zine‐Eddine; Martinez, Guillaume; Celse, Tristan; Touré, Aminata; Arnoult, Christophe; Ray, Pierre F.; Coutton, Charles

doi:10.1016/j.beem.2020.101473

Cited by 54 publications

(33 citation statements)

References 105 publications

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“…Currently, the discovery of new candidate genes and causal variants in idiopathic male infertility is a major challenge in the fields of andrology and reproductive medicine. The recent development of high throughput sequencing (HTS) techniques and the availability of WES for research and clinical practice allowed for the discovery of several novel candidate genes responsible for spermatogenic defects and male infertility [ 18 , 19 , 20 ]. Non-obstructive azoospermia (NOA) is a frequent and very severe cause of male infertility characterized by a strong genetic basis.…”

Section: Discussionmentioning

confidence: 99%

Combined Use of Whole Exome Sequencing and CRISPR/Cas9 to Study the Etiology of Non-Obstructive Azoospermia: Demonstration of the Dispensable Role of the Testis-Specific Genes C1orf185 and CCT6B

Cazin

Neirijnck

Loeuillet

et al. 2021

Cells

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The genetic landscape of male infertility is highly complex. It is estimated that at least 4000 genes are involved in human spermatogenesis, but only few have so far been extensively studied. In this study, we investigated by whole exome sequencing two cases of idiopathic non-obstructive azoospermia (NOA) due to severe hypospermatogenesis. After variant filtering and prioritizing, we retained for each patient a homozygous loss-of-function (LoF) variant in a testis-specific gene, C1orf185 (c.250C>T; p.Gln84Ter) and CCT6B (c.615-2A>G), respectively. Both variants are rare according to the gnomAD database and absent from our local control cohort (n = 445). To verify the implication of these candidate genes in NOA, we used the CRISPR/Cas9 system to invalidate the mouse orthologs 4930522H14Rik and Cct6b and produced two knockout (KO) mouse lines. Sperm and testis parameters of homozygous KO adult male mice were analyzed and compared with those of wild-type animals. We showed that homozygous KO males were fertile and displayed normal sperm parameters and a functional spermatogenesis. Overall, these results demonstrate that not all genes highly and specifically expressed in the testes are essential for spermatogenesis, and in particular, we conclude that bi-allelic variants of C1orf185 and CCT6B are most likely not to be involved in NOA and male fertility.

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Section: Discussionmentioning

confidence: 99%

Combined Use of Whole Exome Sequencing and CRISPR/Cas9 to Study the Etiology of Non-Obstructive Azoospermia: Demonstration of the Dispensable Role of the Testis-Specific Genes C1orf185 and CCT6B

Cazin

Neirijnck

Loeuillet

et al. 2021

Cells

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“…In humans, deletion of the DPY19L2 gene leads to globozoospermia, a condition in which spermatozoa show a monomorphic rounded head. Globozoospermic sperm are unable to adhere to or penetrate the zona pellucida, leading to primary infertility (45). nuclear pole.…”

Section: The Nuclear Membranementioning

confidence: 99%

Sperm bauplan and function and underlying processes of sperm formation and selection

Teves

Roldán

2022

Physiological Reviews

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The spermatozoon is a highly differentiated and polarized cell, with two main structures: the head, containing a haploid nucleus and the acrosomal exocytotic granule, and the flagellum, which generates energy and propels the cell; both structures are connected by the neck. The sperm's main aim is to participate in fertilization, thus activating development. Despite this common bauplan and function there is an enormous diversity in structure and performance of sperm cells. For example, mammalian spermatozoa may exhibit several head patterns and overall sperm lengths ranging from ~30 to 350 µm. Mechanisms of transport in the female tract, preparation for fertilization, and recognition and interaction with the oocyte also show considerable variation. There has been much interest in understanding the origin of this diversity, both in evolutionary terms and in relation to mechanisms underlying sperm differentiation in the testis. Here, relationships between sperm bauplan and function are examined at two levels. First, analyzing the selective forces that drive changes in sperm structure and physiology to understand the adaptive values of this variation and impact on male reproductive success. Second, examining cellular and molecular mechanisms of sperm formation in the testis that may explain how differentiation can give rise to such a wide array of sperm forms and functions.

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“…In addition, validation of newly-identified variants through functional experiments has greatly benefited from the ability to generate mouse knock-out models using CRISPR technology 13 and the use of novel model organisms like Trypanosoma brucei to study specific phenotypes, such as multiple morphological abnormalities of the [sperm] flagella (MMAF) syndrome [14][15][16] . These developments have resulted in a diagnostic yield, based on known genetic causes, explaining about 50% of cases of rare qualitative sperm defects like globozoospermia, acephalic, or MMAF syndromes [17][18] . In contrast, the diagnostic yield for quantitative sperm abnormalities such as oligozoospermia or azoospermia remains below 20%, even though these are the most common forms of male infertility 8,12,19 .…”

Section: Main Textmentioning

confidence: 99%

Oligogenic heterozygous inheritance of sperm abnormalities in mouse

Martinez

Coutton

Loeuillet

et al. 2021

Preprint

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Male infertility is an important health concern that is expected to have a major genetic etiology. Although high-throughput sequencing has linked gene defects to more than 50% of rare and severe sperm anomalies, less than 20% of common and moderate forms are explained. We hypothesized that this low success rate could at least be partly due to oligogenic defects – the accumulation of several rare heterozygous variants in distinct, but functionally connected, genes. Here, we compared fertility and sperm parameters in male mice harboring one to four heterozygous truncating mutations of genes linked to multiple morphological anomalies of the flagellum (MMAF) syndrome. Results indicated progressively deteriorating sperm morphology and motility with increasing numbers of heterozygous mutations. This first evidence of oligogenic inheritance in failed spermatogenesis strongly suggests that oligogenic heterozygosity could explain a significant proportion of asthenoteratozoospermia cases. The findings presented pave the way to further studies in mice and man.

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Genetics of teratozoospermia: Back to the head

Cited by 54 publications

References 105 publications

Combined Use of Whole Exome Sequencing and CRISPR/Cas9 to Study the Etiology of Non-Obstructive Azoospermia: Demonstration of the Dispensable Role of the Testis-Specific Genes C1orf185 and CCT6B

Combined Use of Whole Exome Sequencing and CRISPR/Cas9 to Study the Etiology of Non-Obstructive Azoospermia: Demonstration of the Dispensable Role of the Testis-Specific Genes C1orf185 and CCT6B

Sperm bauplan and function and underlying processes of sperm formation and selection

Oligogenic heterozygous inheritance of sperm abnormalities in mouse

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