Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency

Demain, Leigh A.M.; Boetje, Eline; Edgerley, Jonathan J.; Miles, Emma; Fitzgerald, Cheryl; Busby, Gail; Beaman, Glenda M.; O’Sullivan, James; O’Keefe, Raymond T.

doi:10.1016/j.rbmo.2021.07.003

Cited by 5 publications

(5 citation statements)

References 8 publications

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“…Our patient presented with primary amenorrhea, absence of breast development, hypoplasia of the uterus, osteoporosis and normal height. These clinical features were also reported in other individuals carrying STAG3 pathogenic variants [6,8,13,[15][16][17][18][19]. The hormone replacement therapy (HRT) allowed for puberty to be induced and for the patient to achieve complete secondary sexual characteristics, adequate growth, uterine development and menstrual fluxes.…”

Section: Discussionmentioning

confidence: 62%

“…A LCSH refers to a disomic long homozygous stretch and is used here instead of LOH as the latter describes an event where heterozygosity was originally present and now is lost. This region contained 127 OMIM genes (Figure 2A) among which the best candidate to explain the patient's phenotype was STAG3, whose biallelic mutations had been previously detected in patients with autosomal recessive POI [6,8,13,[15][16][17][18][19].…”

Section: Resultsmentioning

confidence: 99%

“…Up to date, only 11 variants in STAG3 have been reported as genetic causes of POI in eight pedigrees (Figure 3) [6,8,13,[15][16][17][18][19] with a predicted loss of function effect in most cases. The STAG3 frameshift variant identified here is a 4-bp deletion in exon 30 and the resulting transcript would either undergo nonsense-mediated decay [31] or result in a truncated protein devoid of the C-terminal domain similarly to a previously described frameshift mutation truncating the last 206 C-terminal residues in exon 28 [13].…”

Section: Discussionmentioning

confidence: 99%

“…Pathogenic variants in STAG3 (stromal antigen 3), which encodes a subunit of the cohesin complex participating to sister chromatid pairing during meiosis, have been identified as a rare POI monogenic cause. To date STAG3 biallelic variants have been reported in eight families worldwide, five of which were consanguineous pedigree [6,8,13,[15][16][17][18][19]. All the affected women had isolated POI except for a patient belonging to a Palestinian family [6] who presented simultaneous bilateral ovarian tumors.…”

Section: Introductionmentioning

confidence: 99%

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A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

Mellone

Zavattaro

Vurchio

et al. 2021

Genes

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Primary ovarian insufficiency (POI) refers to an etiologically heterogeneous disorder characterized by hypergonadotropic hypogonadism that represents a major cause of infertility in women under 40 years of age. Most cases are apparently sporadic, but about 10–15% have an affected first-degree relative, indicating a genetic etiology. Pathogenic variations in genes involved in development, meiosis and hormonal signaling have been detected in the hereditary form of the disorder. However, most cases of POI remain unsolved even after exhaustive investigation. A 19-year-old Senegalese female affected by non-syndromic POI presented with primary amenorrhoea and answered well to the hormonal induction of puberty. In order to investigate the presence of a genetic defect, aCGH-SNP analysis was performed. A 13.5 Mb long contiguous stretch of homozygosity (LCSH) was identified on chromosome 7q21.13-q22.1 where the exome sequencing revealed a novel homozygous 4-bp deletion (c.3381_3384delAGAA) in STAG3. Pathogenic variants in this gene, encoding for a meiosis-specific protein, have been previously reported as the cause of POI in only eight families and recently as the cause of infertility in a male. The here-identified mutation leads to the truncation of the last 55 amino acids, confirming the important role in meiosis of the STAG3 C-terminal domain.

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Section: Discussionmentioning

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

Mellone

Zavattaro

Vurchio

et al. 2021

Genes

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“…The cohesin complex regulates sister chromatid cohesion and synaptonemal complex (SC) formation and is composed of the meiosisspecific subunits STAG3, RAD21L, and SMC1β and the nonspecific subunits SMC3 and REC8 [8]. STAG3 aberrations have been identified to cause a rare monogenic type of POI [9][10][11][12][13][14][15][16][17][18]. The chromosome axis forms a platform for SC assembly, which plays a central role in homologous pairing, recombination, and chromosome segregation.…”

Section: Introductionmentioning

confidence: 99%

SRSF1 regulates primordial follicle formation and number determination during meiotic prophase I

Sun

Chen

et al. 2023

BMC Biol

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Background Ovarian folliculogenesis is a tightly regulated process leading to the formation of functional oocytes and involving successive quality control mechanisms that monitor chromosomal DNA integrity and meiotic recombination. A number of factors and mechanisms have been suggested to be involved in folliculogenesis and associated with premature ovarian insufficiency, including abnormal alternative splicing (AS) of pre-mRNAs. Serine/arginine-rich splicing factor 1 (SRSF1; previously SF2/ASF) is a pivotal posttranscriptional regulator of gene expression in various biological processes. However, the physiological roles and mechanism of SRSF1 action in mouse early-stage oocytes remain elusive. Here, we show that SRSF1 is essential for primordial follicle formation and number determination during meiotic prophase I. Results The conditional knockout (cKO) of Srsf1 in mouse oocytes impairs primordial follicle formation and leads to primary ovarian insufficiency (POI). Oocyte-specific genes that regulate primordial follicle formation (e.g., Lhx8, Nobox, Sohlh1, Sohlh2, Figla, Kit, Jag1, and Rac1) are suppressed in newborn Stra8-GFPCre Srsf1Fl/Fl mouse ovaries. However, meiotic defects are the leading cause of abnormal primordial follicle formation. Immunofluorescence analyses suggest that failed synapsis and an inability to undergo recombination result in fewer homologous DNA crossovers (COs) in the Srsf1 cKO mouse ovaries. Moreover, SRSF1 directly binds and regulates the expression of the POI-related genes Six6os1 and Msh5 via AS to implement the meiotic prophase I program. Conclusions Altogether, our data reveal the critical role of an SRSF1-mediated posttranscriptional regulatory mechanism in the mouse oocyte meiotic prophase I program, providing a framework to elucidate the molecular mechanisms of the posttranscriptional network underlying primordial follicle formation.

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Homozygous missense variants in BMPR15 can result in primary ovarian insufficiency

Demain

Metcalfe

Boetje

et al. 2022

Reproductive BioMedicine Online

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Biallelic loss of function variants in STAG3 result in primary ovarian insufficiency

Cited by 5 publications

References 8 publications

A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

A Long Contiguous Stretch of Homozygosity Disclosed a Novel STAG3 Biallelic Pathogenic Variant Causing Primary Ovarian Insufficiency: A Case Report and Review of the Literature

SRSF1 regulates primordial follicle formation and number determination during meiotic prophase I

Homozygous missense variants in BMPR15 can result in primary ovarian insufficiency

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