Novel STAG3 variant associated with primary ovarian insufficiency and non-obstructive azoospermia in an Iranian consanguineous family

Akbari, Arvand; Tabatabaei, Seyedeh Zoha; Salehi, Najmeh; Padidar, Kimiya; Almadani, Navid; Gilani, Mohammad Ali Sadighi; Mashayekhi, Mehri; Motevaseli, Elahe; Totonchi, Mehdi

doi:10.1016/j.gene.2022.146281

Cited by 10 publications

(5 citation statements)

References 88 publications

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“…In recent years, high-throughput sequencing technology has enabled the analysis of genetic information in patients with POI, leading to the identification of pathogenic genes closely related to POI. Several genes have been associated with POI, such as BRCA2 [ 7 ], C14orf39 [ 8 ], ZSWIM7 [ 9 ], PSMC3IP [ 10 ], NHEJ1 [ 11 ], HSF2BP [ 12 ], MSH4 [ 13 ], MSH5 [ 14 ], FIGLA [ 15 ], NOBOX [ 16 ], STAG3 [ 17 ], MCM8/9 [ 18 ], HFM1 [ 19 ], EIF4ENIF1 [ 20 ], KHDRBS1 [ 21 ], NOTCH2 [ 22 ], BNC1 [ 23 ]. These genes participate in various activities such as folliculogenesis, gonadogenesis, oocyte maturation, DNA damage, meiosis, cell apoptosis, and various other functions [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2

Fan,

Chen,

Chu

et al. 2024

J Ovarian Res

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Background Premature ovarian insufficiency (POI) is a severe disorder leading to female infertility. Genetic mutations are important factors causing POI. TP63-truncating mutation has been reported to cause POI by increasing germ cell apoptosis, however what factors mediate this apoptosis remains unclear. Methods Ninety-three patients with POI were recruited from Beijing Obstetrics and Gynecology Hospital, Capital Medical University. Whole-exome sequencing (WES) was performed for each patient. Sanger sequencing was used to confirm potential causative genetic variants. A minigene assay was performed to determine splicing effects of TP63 variants. A TP63-truncating plasmid was constructed. Real-time quantitative PCR, western blot analyses, dual luciferase reporter assays, immunofluorescence staining, and cell apoptosis assays were used to study the underlying mechanism of a TP63-truncating mutation causing POI. Results By WES of 93 sporadic patients with POI, we found a 14-bp deletion covering the splice site in the TP63 gene. A minigene assay demonstrated that the 14-bp deletion variant led to exon 13 skipping during TP63 mRNA splicing, resulting in the generation of a truncated TP63 protein (TP63-mut). Overexpression of TP63-mut accelerated cell apoptosis. Mechanistically, the TP63-mut protein could bind to the promoter region of CLCA2 and activate the transcription of CLCA2 several times compared to that of the TP63 wild-type protein. Silencing CLCA2 using a specific small interfering RNA (siRNA) or inhibiting the Ataxia Telangiectasia Mutated (ATM) pathway using the KU55933 inhibitor attenuated cell apoptosis caused by TP63-mut protein expression. Conclusion Our findings revealed a crucial role for CLCA2 in mediating apoptosis in POI pathogenesis, and suggested that CLCA2 is a potential therapeutic target for POI.

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Section: Introductionmentioning

confidence: 99%

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2

Fan,

Chen,

Chu

et al. 2024

J Ovarian Res

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“…Given the relevance of meiotic cohesins in SC assembly during prophase I and the shared steps of meiosis I in both oogenesis and spermatogenesis, it is not surprising that STAG3 variants have also been identified in men affected by nonobstructive azoospermia (NOA) [75][76][77]. In fact, very recently, an in-frame STAG3 variant associated with both NOA and POI was reported for the first time, as we had previously predicted [28,78]. Furthermore, recent studies have identified genetic variants of the other meiotic-specific cohesins SMC1β, REC8, and RAD21L associated with infertility phenotypes including POI and NOA [76,[79][80][81][82].…”

Section: Infertilitymentioning

confidence: 86%

Synaptonemal Complex in Human Biology and Disease

Llano

Pendás

2023

Cells

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The synaptonemal complex (SC) is a meiosis-specific multiprotein complex that forms between homologous chromosomes during prophase of meiosis I. Upon assembly, the SC mediates the synapses of the homologous chromosomes, leading to the formation of bivalents, and physically supports the formation of programmed double-strand breaks (DSBs) and their subsequent repair and maturation into crossovers (COs), which are essential for genome haploidization. Defects in the assembly of the SC or in the function of the associated meiotic recombination machinery can lead to meiotic arrest and human infertility. The majority of proteins and complexes involved in these processes are exclusively expressed during meiosis or harbor meiosis-specific subunits, although some have dual functions in somatic DNA repair and meiosis. Consistent with their functions, aberrant expression and malfunctioning of these genes have been associated with cancer development. In this review, we focus on the significance of the SC and their meiotic-associated proteins in human fertility, as well as how human genetic variants encoding for these proteins affect the meiotic process and contribute to infertility and cancer development.

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“…The etiology of POI could be autoimmune (4%–30%) ( Kirshenbaum and Orvieto, 2019 ) or genetic ( França and Mendonca, 2019 ), although the majority remains unknown. A few case reports showed a biallelic pathogenic variant in STAG3 , a cohesion gene, affected the meiosis-specific cohesion complexes, which might lead to premature ovarian failure ( Caburet et al, 2014 ; Colombo et al, 2017 ; Akbari et al, 2022 ). Other meiosis-specific complexes in cohesin, including REC8, RAD21L, and SMC1β, have been shown to be associated with abnormal oocyte development ( Caburet et al, 2014 ; Ward et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: The evolving phenotype of ESCO2 spectrum disorder in a 15-year-old Malaysian child

Tae,

RA,

Thong

2024

Front. Genet.

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ESCO2 spectrum disorder is an autosomal recessive developmental disorder characterized by growth retardation, symmetrical mesomelic limb malformation, and distinctive facies with microcephaly, with a wide phenotypic continuum that ranges from Roberts syndrome (MIM #268300) at the severe end to SC phocomelia (MIM #269000) at the milder end. ESCO2 encodes a 601-amino acid protein belonging to the Eco1/Ctf7 family of acetyltransferases that is involved in the establishment of sister chromatid cohesion, which is essential for accurate chromosome segregation and genomic stability and thus belongs to a group of disorders called “cohesinopathies”. We describe a 15-year-old Malaysian female who presented with the characteristic triad of ESCO2 spectrum disorder, with an equivocal chromosomal breakage study and normal karyotyping findings. She was initially suspected to have mosaic Fanconi anemia but whole exome sequencing (WES) showed a likely pathogenic homozygous splice variant c.955 + 2_955+5del in the ESCO2 gene. During the 15-year diagnostic odyssey, she developed type 2 diabetes mellitus, primary ovarian insufficiency, increased optic cup-to-disc ratio with tortuous vessels bilaterally, and an evolving but distinct facial and skin hypopigmentation phenotype. Of note, there was an absence of learning disabilities. Our findings provide further evidence for ESCO2 spectrum disorder in an Asian child and contribute to defining the clinical and radiographic spectrum.

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Novel STAG3 variant associated with primary ovarian insufficiency and non-obstructive azoospermia in an Iranian consanguineous family

Cited by 10 publications

References 88 publications

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2

TP63 truncating mutation causes increased cell apoptosis and premature ovarian insufficiency by enhanced transcriptional activation of CLCA2

Synaptonemal Complex in Human Biology and Disease

Case report: The evolving phenotype of ESCO2 spectrum disorder in a 15-year-old Malaysian child

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