Loss‐of‐function mutations in centrosomal protein 112 is associated with human acephalic spermatozoa phenotype

Sha, Yanwei; Wang, Xiong; Yuan, Jinting; Zhu, Xingshen; Su, Zhiying; Zhang, Xuequan; Xu, Xiaohui; Wei, Xiaoli

doi:10.1111/cge.13662

Cited by 28 publications

(22 citation statements)

References 34 publications

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“…Centrosomal protein 112 (CEP112), a coiled-coil domain containing centrosomal protein and member of the cell division control protein had the highest SpliZ-pseudotime correlation. It is highly expressed in testes and is essential for maintaining sperm function: loss-of-function mutations in CEP112 have recently been associated with male infertility 47 . Strikingly, the same 3' splice site and 5' splice sites identified by SpliZsites are orthologous and affect the apolipoprotein domain, a protein involved in the delivery of lipid between cell membranes an is critical for the sperm development and fertility 48 (Figure 7D).…”

Section: The Spliz Discovers Conserved Alternative Splicing In Mammalian Spermatogenesismentioning

confidence: 99%

RNA splicing programs define tissue compartments and cell types at single cell resolution

Olivieri¹,

Dehghannasiri²,

Jang³

et al. 2021

Preprint

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More than 95% of human genes are alternatively spliced. Yet, the extent splicing is regulated at single-cell resolution has remained controversial due to both available data and methods to interpret it. We apply the SpliZ, a new statistical approach that is agnostic to transcript annotation, to detect cell-type-specific regulated splicing in > 110K carefully annotated single cells from 12 human tissues. Using 10x data for discovery, 9.1% of genes with computable SpliZ scores are cell-type specifically spliced. These results are validated with RNA FISH, single cell PCR, and in high throughput with Smart-seq2. Regulated splicing is found in ubiquitously expressed genes such as actin light chain subunit MYL6 and ribosomal protein RPS24, which has an epithelial-specific microexon. 13% of the statistically most variable splice sites in cell-type specifically regulated genes are also most variable in mouse lemur or mouse. SpliZ analysis further reveals 170 genes with regulated splicing during sperm development using, 10 of which are conserved in mouse and mouse lemur. The statistical properties of the SpliZ allow model-based identification of subpopulations within otherwise indistinguishable cells based on gene expression, illustrated by subpopulations of classical monocytes with stereotyped splicing, including an un-annotated exon, in SAT1, a Diamine acetyltransferase. Together, this unsupervised and annotation-free analysis of differential splicing in ultra high throughput droplet-based sequencing of human cells across multiple organs establishes splicing is regulated cell-type-specifically independent of gene expression.

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Section: The Spliz Discovers Conserved Alternative Splicing In Mammalian Spermatogenesismentioning

confidence: 99%

RNA splicing programs define tissue compartments and cell types at single cell resolution

Olivieri¹,

Dehghannasiri²,

Jang³

et al. 2021

Preprint

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“…Mutations in several different genes are known to generate this phenotype. Thus, polyamine modulated factor 1 binding protein 1 ( PMFBP1 ), testis specific 10 ( TSGA10 ), Sad1 and UNC84 domain containing 5 ( SUN5 ), bromodomain testis associated ( BRDT ) and centrosomal protein 112 ( CEP112 ) have all recently been implicated in the etiology of this condition ( 21 – 23 ). The reason why so many different mutations appear to be involved in the creation of acephalic spermatozoa is a reflection of the inordinate complexity of the head-tail coupling apparatus in these cells ( 24 ).…”

Section: Genetic Causes Of Male Infertilitymentioning

confidence: 99%

The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis?

Aitken

Baker

2020

Front. Endocrinol.

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Despite the high prevalence of male infertility, very little is known about its etiology. In recent years however, advances in gene sequencing technology have enabled us to identify a large number of rare single point mutations responsible for impeding all aspects of male reproduction from its embryonic origins, through the endocrine regulation of spermatogenesis to germ cell differentiation and sperm function. Such monogenic mutations aside, the most common genetic causes of male infertility are aneuploidies such as Klinefelter syndrome and Y-chromosome mutations which together account for around 20-25% of all cases of non-obstructive azoospermia. Oxidative stress has also emerged as a major cause of male fertility with at least 40% of patients exhibiting some evidence of redox attack, resulting in high levels of lipid peroxidation and oxidative DNA damage in the form of 8-hydroxy-2'-deoxyguanosine (8OHdG). The latter is highly mutagenic and may contribute to de novo mutations in our species, 75% of which are known to occur in the male germ line. An examination of 8OHdG lesions in the human sperm genome has revealed ∼9,000 genomic regions vulnerable to oxidative attack in spermatozoa. While these oxidized bases are generally spread widely across the genome, a particular region on chromosome 15 appears to be a hot spot for oxidative attack. This locus maps to a genetic location which has linkages to male infertility, cancer, imprinting disorders and a variety of behavioral conditions (autism, bipolar disease, spontaneous schizophrenia) which have been linked to the age of the father at the moment of conception. We present a hypothesis whereby a number of environmental, lifestyle and clinical factors conspire to induce oxidative DNA damage in the male germ line which then triggers the formation de novo mutations which can have a major impact on the health of the offspring including their subsequent fertility.

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“…For example, we already know that genetic defects in sperm phospholipase C zeta impair human oocyte activation and fertilization, 95 while mutations in CEP112 (centriolar protein 112) as well as SUN5 (Sad1 and UNC84 domain containing 5) lead to headless, acephalic spermatozoa. 96,97 Fertilization failure has also been associated with mutations in CATPSERE (CatSper-epsilon), a component of the sperm calcium channel, 98 as well as polymorphisms in the mitochondrial genes MT-ATP6 and MT-CYB. 99 Furthermore, changes in sperm mitochondrial DNA copy number (mtDNAcn) and deletion rate (mtDNAdel) have also been associated with impaired fertilization in an ART setting.…”

Section: Additional Genetic Factorsmentioning

confidence: 99%

The Male Is Significantly Implicated as the Cause of Unexplained Infertility

Aitken

2020

Semin Reprod Med

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Male 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.

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Loss‐of‐function mutations in centrosomal protein 112 is associated with human acephalic spermatozoa phenotype

Cited by 28 publications

References 34 publications

RNA splicing programs define tissue compartments and cell types at single cell resolution

RNA splicing programs define tissue compartments and cell types at single cell resolution

The Role of Genetics and Oxidative Stress in the Etiology of Male Infertility—A Unifying Hypothesis?

The Male Is Significantly Implicated as the Cause of Unexplained Infertility

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