Mutation in TDRD9 causes non-obstructive azoospermia in infertile men

Arafat, Maram; Har-Vardi, Iris; Harlev, Avi; Levitas, Eliahu; Zeadna, Atif; Abofoul‐Azab, Maram; Dyomin, Victor; Sheffield, Val C.; Lunenfeld, Eitan; Huleihel, Mahmoud; Parvari, Ruti

doi:10.1136/jmedgenet-2017-104514

Cited by 111 publications

(60 citation statements)

References 39 publications

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“…Two separate studies in the population of Iran and China reported a significant relationship between HIWI2 gene rs508485 polymorphism and increased risk of spermatogenesis defects [33,34]. Arafat et al reported the relationship between the deletion frameshift mutation in TDRD9 and NOA [35]. In present study, expression of TDRD9 like TDRD1 showed a significantly decreased in the MA samples compared with OA samples.…”

Section: Discussionsupporting

confidence: 52%

Testicular expression of TDRD1, TDRD5, TDRD9 and TDRD12 in azoospermia

et al. 2020

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Background: Tudor domain-containing proteins (TDRDs) play a critical role in piRNA biogenesis and germ cell development. piRNAs, small regulatory RNAs, act by silencing of transposons during germline development and it has recently been shown in animal model studies that defects in TDRD genes can lead to sterility in males. Methods: Here we evaluate gene and protein expression levels of four key TDRDs (TDRD1, TDRD5, TDRD9 and TDRD12) in testicular biopsy samples obtained from men with obstructive azoospermia (OA, n = 29), as controls, and various types of non-obstructive azoospermia containing hypospermatogenesis (HP, 28), maturation arrest (MA, n = 30), and Sertoli cell-only syndrome (SCOS, n = 32) as cases. One-way ANOVA test followed by Dunnett's multiple comparison post-test was used to determine inter-group differences in TDRD gene expression among cases and controls. Results: The results showed very low expression of TDRD genes in SCOS specimens. Also, the expression of TDRD1 and TDRD9 genes were lower in MA samples compared to OA samples. The expression of TDRD5 significantly reduced in SCOS, MA and HP specimens than the OA specimens. Indeed, TDRD12 exhibited a very low expression in HP specimens in comparison to OA specimens. All these results were confirmed by Western blot technique.Conclusion: TDRDs could be very important in male infertility, which should be express in certain stages of spermatogenesis.

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Section: Discussionsupporting

confidence: 52%

Testicular expression of TDRD1, TDRD5, TDRD9 and TDRD12 in azoospermia

et al. 2020

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“…Azoospermia is the main cause of male infertility. To date, mutations on several genes, including SYCP3 ,5 NR5A1 ,6 TDRD9 ,7 TAF4B and ZMYND15 ,8 TEX11 ,9 10 DMC1 ,11 TDRD7 ,12 MAGEB4 ,13 SYCE1 ,14 SOHLH1 15 and MCM8 ,16 have been identified as the causes of azoospermia. However, the genetic basis of this defect in most infertility cases remains unknown 2–4 12…”

Section: Introductionmentioning

confidence: 99%

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

et al. 2018

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BackgroundMeiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities.MethodsHomozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system.ResultsWe identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility.ConclusionA XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

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“…TDRD9 (tudor domain containing 9) also showed increased interaction between the hubs, in disease states, compared with healthy controls. Expression of this entity has been described in gametogenesis with expression in testis and thyroid (103)(104)(105)(106), its association with immune cells or processes has not previously been reported. Its primary function is in transposon silencing and progression of spermatogenesis (107), through an ATPase activity and interaction with PIWI proteins.…”

Section: Tdrd9mentioning

confidence: 92%

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

et al. 2020

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Sepsis is defined as dysregulated host response caused by systemic infection, leading to organ failure. It is a life-threatening condition, often requiring admission to an intensive care unit (ICU). The causative agents and processes involved are multifactorial but are characterized by an overarching inflammatory response, sharing elements in common with severe inflammatory response syndrome (SIRS) of non-infectious origin. Sepsis presents with a range of pathophysiological and genetic features which make clinical differentiation from SIRS very challenging. This may reflect a poor understanding of the key gene inter-activities and/or pathway associations underlying these disease processes. Improved understanding is critical for early differential recognition of sepsis and SIRS and to improve patient management and clinical outcomes. Judicious selection of gene biomarkers suitable for development of diagnostic tests/testing could make differentiation of sepsis and SIRS feasible. Here we describe a methodologic framework for the identification and validation of biomarkers in SIRS, sepsis and septic shock patients, using a 2-tier gene screening, artificial neural network (ANN) data mining technique, using previously published gene expression datasets. Eight key hub markers have been identified which may delineate distinct, core disease processes and which show potential for informing underlying immunological and pathological processes and thus patient stratification and treatment. These do not show sufficient fold change differences between the different disease states to be useful as primary diagnostic biomarkers, but are instrumental in identifying candidate pathways and other associated biomarkers for further exploration.

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Mutation in TDRD9 causes non-obstructive azoospermia in infertile men

Cited by 111 publications

References 39 publications

Testicular expression of TDRD1, TDRD5, TDRD9 and TDRD12 in azoospermia

Testicular expression of TDRD1, TDRD5, TDRD9 and TDRD12 in azoospermia

XRCC2 mutation causes meiotic arrest, azoospermia and infertility

Development of a Bioinformatics Framework for Identification and Validation of Genomic Biomarkers and Key Immunopathology Processes and Controllers in Infectious and Non-infectious Severe Inflammatory Response Syndrome

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