Detection of a mutation in the intron of Sperm-specific glyceraldehyde-3-phosphate dehydrogenase gene in patients with fibrous sheath dysplasia of the sperm flagellum

Elkina, Yu. L.; Kuravsky, M. L.; Брагина, Е. Е.; Kurilo, L. F.; Khayat, S. Sh.; Sukhomlinova, M. Y.; Schmalhausen, E.V.

doi:10.1111/and.12606

Cited by 11 publications

(9 citation statements)

References 31 publications

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“…Voltage-dependent anion channel 3(Vdac3) is a non-specific hollow porin in the outer mitochondrial membrane of sperm flagella. ATP levels significantly dropped in the Gapdhs-and Vdac3-null mice leading to non-progressive and weak motility of sperm flagella [69,[76][77][78]. However, for majority of patients with severe asthenozoospermia, the hereditary pathogenic variants, if present, remain largely undetermined, and further screening and functional studies are required to fully understand the pathogenesis of severe asthenozoospermia.…”

Section: Asthenozoospermiamentioning

confidence: 99%

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Azhar¹,

Altaf²,

Uddin³

et al. 2021

Int. J. Biol. Sci.

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Declined quality and quantity of sperm is currently the major cause of patients suffering from infertility. Male germ cell development is spatiotemporally regulated throughout the whole developmental process. While it has been known that exogenous factors, such as environmental exposure, diet and lifestyle, et al, play causative roles in male infertility, recent progress has revealed abundant genetic mutations tightly associated with defective male germline development. In mammals, male germ cells undergo dramatic morphological change (i.e., nuclear condensation) and chromatin remodeling during post-meiotic haploid germline development, a process termed spermiogenesis; However, the molecular machinery players and functional mechanisms have yet to be identified. To date, accumulated evidence suggests that disruption in any step of haploid germline development is likely manifested as fertility issues with low sperm count, poor sperm motility, aberrant sperm morphology or combined. With the continually declined cost of next-generation sequencing and recent progress of CRISPR/Cas9 technology, growing studies have revealed a vast number of disease-causing genetic variants associated with spermiogenic defects in both mice and humans, along with mechanistic insights partially attained and validated through genetically engineered mouse models (GEMMs). In this review, we mainly summarize genes that are functional at post-meiotic stage. Identification and characterization of deleterious genetic variants should aid in our understanding of germline development, and thereby further improve the diagnosis and treatment of male infertility.

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Section: Asthenozoospermiamentioning

confidence: 99%

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Azhar¹,

Altaf²,

Uddin³

et al. 2021

Int. J. Biol. Sci.

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show abstract

“…The principal piece contains the fibrous sheath and the midpiece contains mitochondria, which produce energy for sperm motility [ 6 ]. The sperm tail axoneme is often disintegrated when ODFs and the fibrous sheath are malformed [ 7 , 8 , 9 ]. The midpiece and principal piece are separated by a diffusion barrier called the annulus ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Jayasena

Sironen

2021

Diagnostics

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Primary ciliary dyskinesia (PCD), a disease caused by the malfunction of motile cilia, manifests mainly with chronic recurrent respiratory infections. In men, PCD is also often associated with infertility due to immotile sperm. Since causative mutations for PCD were identified in over 50 genes, the role of these genes in sperm development should be investigated in order to understand the effect of PCD mutations on male fertility. Previous studies showed that different dynein arm heavy chains are present in respiratory cilia and sperm flagellum, which may partially explain the variable effects of mutations on airways and fertility. Furthermore, recent studies showed that male reproductive tract motile cilia may play an important part in sperm maturation and transport. In some PCD patients, extremely low sperm counts were reported, which may be due to motile cilia dysfunction in the reproductive tract rather than problems with sperm development. However, the exact roles of PCD genes in male fertility require additional studies, as do the treatment options. In this review, we discuss the diagnostic and treatment options for men with PCD based on the current knowledge.

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“…As an important component of FS, AKAP4 is required for anchoring signal transduction proteins, and the targeted disruption of mouse Akap4 caused defects in the sperm flagella and motility 1. In addition, a sperm-specific glyceraldehyde-3-phosphate dehydrogenase located at the FS plays an important role in regulating the switch between different energy-producing pathways and is required for sperm motility and male fertility 7 8. These previous reports supported the important role of FS-associated proteins in spermatogenesis.…”

Section: Introductionmentioning

confidence: 62%

Homozygous variants inAKAP3induce asthenoteratozoospermia and male infertility

et al. 2022

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BackgroundAs a common type of asthenoteratozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF) can cause male infertility. Previous studies have revealed genetic factors as a major cause of MMAF. The known MMAF-associated genes are involved in the mitochondrial sheath, outer dense fibre or axoneme of the sperm flagella. These findings indicate the genetic heterogeneity of MMAF.Methods and resultsHere, we conducted genetic analyses using whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants of AKAP3 (A-kinase anchoring protein 3) were identified in two MMAF-affected men from unrelated families. One AKAP3 variant was a frameshift (c.2286_2287del, p.His762Glnfs*22) and the other variant was a missense mutation (c.44G>A, p.Cys15Tyr), which was predicted to be damaging by multiple bioinformatics tools. Further western blotting and immunofluorescence assays revealed the absence of AKAP3 in the spermatozoa from the man harbouring the homozygous frameshift variant, whereas the expression of AKAP3 was markedly reduced in the spermatozoa of the man with the AKAP3 missense variant p.Cys15Tyr. Notably, the clinical outcomes after intracytoplasmic sperm injection (ICSI) were divergent between these two cases, suggesting a possibility of AKAP3 dosage-dependent prognosis of ICSI treatment.ConclusionsOur study revealed AKAP3 as a novel gene involved in human asthenoteratozoospermia.

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Detection of a mutation in the intron of Sperm-specific glyceraldehyde-3-phosphate dehydrogenase gene in patients with fibrous sheath dysplasia of the sperm flagellum

Cited by 11 publications

References 31 publications

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Towards Post-Meiotic Sperm Production: Genetic Insight into Human Infertility from Mouse Models

Diagnostics and Management of Male Infertility in Primary Ciliary Dyskinesia

Homozygous variants inAKAP3induce asthenoteratozoospermia and male infertility

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