Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia

Zhang, Yuxiang; Liu, Nachuan; Tao, Jing; Ji, Zhiyong; Yang, Chao; Zhao, Liangyu; Tian, Ruhui; Chen, Huixing; Huang, Yuhua; Zhi, Erlei; Ou, Ningjing; Bai, Haowei; Zhou, Yuchuan; Li, Zheng; Yao, Chencheng

doi:10.3389/fgene.2021.799886

Cited by 11 publications

(6 citation statements)

References 32 publications

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“…ICL can terminate normal DNA unwinding, causing replication and transcription abnormalities and leading to meiosis arrest, chromosome breakage, and abnormal chromosome binding, significantly damaging the cell's proliferative ability and causing abnormal germ cell development (124, 125). Zhang et al found that the Sertoli cell-only syndrome phenotype of NOA may be related to ICL repair defects and is associated with DNA replication in germ cells (126). In the upstream of the FA signaling pathway, mutations in the FANCM/A/G/B/C gene have been shown to be associated with human NOA (12,46,47,49,127).…”

Section: The Role Of Icl In Repairing Defects Leading To Noa Occurrencementioning

confidence: 99%

“…Zhang et al. found that the Sertoli cell-only syndrome phenotype of NOA may be related to ICL repair defects and is associated with DNA replication in germ cells ( 126 ). In the upstream of the FA signaling pathway, mutations in the FANCM/A/G/B/C gene have been shown to be associated with human NOA ( 12 , 46 , 47 , 49 , 127 ).…”

Section: The Role Of Icl In Repairing Defects Leading To Noa Occurrencementioning

confidence: 99%

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Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia

Xu,

Zhang,

Wang

et al. 2024

Front. Endocrinol.

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Non-obstructive azoospermia (NOA) is a disease characterized by spermatogenesis failure and comprises phenotypes such as hypospermatogenesis, mature arrest, and Sertoli cell-only syndrome. Studies have shown that FA cross-linked anemia (FA) pathway is closely related to the occurrence of NOA. There are FA gene mutations in male NOA patients, which cause significant damage to male germ cells. The FA pathway is activated in the presence of DNA interstrand cross-links; the key step in activating this pathway is the mono-ubiquitination of the FANCD2-FANCI complex, and the activation of the FA pathway can repair DNA damage such as DNA double-strand breaks. Therefore, we believe that the FA pathway affects germ cells during DNA damage repair, resulting in minimal or even disappearance of mature sperm in males. This review summarizes the regulatory mechanisms of FA-related genes in male azoospermia, with the aim of providing a theoretical reference for clinical research and exploration of related genes.

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Section: The Role Of Icl In Repairing Defects Leading To Noa Occurrencementioning

confidence: 99%

Section: The Role Of Icl In Repairing Defects Leading To Noa Occurrencementioning

confidence: 99%

Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia

Xu,

Zhang,

Wang

et al. 2024

Front. Endocrinol.

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“…Whole exome sequencing (WES) has identified several genes in NOA pedigrees, including DNA meiotic recombinase 1, stromal antigen 3, testis expressed 11, shortage in chiasmata 1, synaptonemal complex central element protein 1, meiosis-specific with an OB-fold coiled-coil domain containing 155, testis expressed 14, testis expressed 15, and X-ray repair cross-complementing 2 [ 14 , 15 ]. This study found Sertoli cell gene expression deficiencies that are involved in spermatogenesis.…”

Section: Introductionmentioning

confidence: 99%

Whole Exome Sequencing and In Silico Analysis of Human Sertoli in Patients with Non-Obstructive Azoospermia

Azizi

Karoii

Skutella

2022

IJMS

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Non-obstructive azoospermia (NOA) is a serious cause of male infertility. The Sertoli cell responds to androgens and takes on roles supporting spermatogenesis, which may cause infertility. This work aims to enhance the genetic diagnosis of NOA via the discovery of new and hub genes implicated in human NOA and to better assess the odds of successful sperm extraction according to the individual’s genotype. Whole exome sequencing (WES) was done on three NOA patients to find key genes involved in NOA. We evaluated genome-wide transcripts (about 50,000 transcripts) by microarray between the Sertoli of non-obstructive azoospermia and normal cells. The microarray analysis of three human cases with different non-obstructive azoospermia revealed that 32 genes were upregulated, and the expressions of 113 genes were downregulated versus the normal case. For this purpose, Enrich Shiny GO, STRING, and Cytoscape online evaluations were applied to predict the functional and molecular interactions of proteins and then recognize the master pathways. The functional enrichment analysis demonstrated that the biological process (BP) terms “inositol lipid-mediated signaling”, “positive regulation of transcription by RNA polymerase II”, and “positive regulation of DNA-templated transcription” significantly changed in upregulated differentially expressed genes (DEGs). The BP investigation of downregulated DEGs highlighted “mitotic cytokinesis”, “regulation of protein-containing complex assembly”, “cytoskeleton-dependent cytokinesis”, and the “peptide metabolic process”. Overrepresented molecular function (MF) terms in upregulated DEGs included “ubiquitin-specific protease binding”, “protease binding”, “phosphatidylinositol trisphosphate phosphatase activity”, and “clathrin light chain binding”. Interestingly, the MF analysis of the downregulated DEGs revealed overexpression in “ATPase inhibitor activity”, “glutathione transferase activity”, and “ATPase regulator activity”. Our findings suggest that these genes and their interacting hub proteins could help determine the pathophysiologies of germ cell abnormalities and infertility.

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“…In humans and mice, FANCM is required for normal fertility and gametogenesis [5–12]. Reports of male patients with biallelic mutations in FANCM revealed sterility characterised by non-obstructive azoospermia and Sertoli cellonly seminiferous epithelium [8, 9, 13].…”

Section: Introductionmentioning

confidence: 99%

Fancm regulates meiotic double-strand break repair pathway choice in mammals

Tsui

Lyu

Novakovic

et al. 2022

Preprint

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Meiotic crossovers are required for accurate chromosome segregation and to produce new allelic combinations. Meiotic crossover numbers are tightly regulated within a narrow range, despite an excess of initiating DNA double-strand breaks. Here, we describe the tumour suppressor FANCM as a meiotic anti-crossover factor in mammals. Crossover analyses with single-gamete and pedigree datasets both reveal a genome-wide increase in crossover frequencies in Fancm-deficient mice. Gametogenesis is heavily perturbed in Fancm loss of function mice, which is consistent with the reproductive defects reported in humans with biallelic FANCM mutations. A portion of the gametogenesis defects can be attributed to the cGAS-STING pathway. Despite the gametogenesis phenotypes in Fancm mutants both sexes were capable of producing offspring. We propose that the anti-crossover function and role in gametogenesis of Fancm are separable and will inform diagnostic pathways for human genomic instability disorders.

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Novel Bi-Allelic Variants of FANCM Cause Sertoli Cell-Only Syndrome and Non-Obstructive Azoospermia

Cited by 11 publications

References 32 publications

Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia

Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia

Whole Exome Sequencing and In Silico Analysis of Human Sertoli in Patients with Non-Obstructive Azoospermia

Fancm regulates meiotic double-strand break repair pathway choice in mammals

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