SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility

Schilit, Samantha L.P.; Menon, Shreya; Friedrich, Corinna; Kammin, Tammy; Wilch, Ellen; Hanscom, Carrie; Jiang, Sizun; Kliesch, Sabine; Talkowski, Michael E.; Tüttelmann, Frank; MacQueen, Amy J.; Morton, Cynthia C.

doi:10.1016/j.ajhg.2019.11.013

Cited by 67 publications

(54 citation statements)

References 103 publications

(136 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, one heterozygous frameshift variant was found for the gene SYCP2 in patient M1686, who carries the TRIM71 variant c.1070C>T/p.(Ala357Val). SYCP2 was recently associated with male infertility ( Schilit et al, 2019 ), and it is thus unlikely that this patient’s TRIM71 variant alone is responsible for his cryptozoospermia, but an oligogenic cause of his phenotype cannot be ruled out. Furthermore, a heterozygous missense variant for the gene NNT was identified in patient M1083, who carries the TRIM71 variant c.1486C>T/p.(Arg496Cys).…”

Section: Resultsmentioning

confidence: 94%

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility

Fernández

Emich

Port

et al. 2021

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

Mutations affecting the germline can result in infertility or the generation of germ cell tumors (GCT), highlighting the need to identify and characterize the genes controlling germ cell development. The RNA-binding protein and E3 ubiquitin ligase TRIM71 is essential for embryogenesis, and its expression has been reported in GCT and adult mouse testes. To investigate the role of TRIM71 in mammalian germ cell embryonic development, we generated a germline-specific conditional Trim71 knockout mouse (cKO) using the early primordial germ cell (PGC) marker Nanos3 as a Cre-recombinase driver. cKO mice are infertile, with male mice displaying a Sertoli cell-only (SCO) phenotype which in humans is defined as a specific subtype of non-obstructive azoospermia characterized by the absence of germ cells in the seminiferous tubules. Infertility in male Trim71 cKO mice originates during embryogenesis, as the SCO phenotype was already apparent in neonatal mice. The in vitro differentiation of mouse embryonic stem cells (ESCs) into PGC-like cells (PGCLCs) revealed reduced numbers of PGCLCs in Trim71-deficient cells. Furthermore, TCam-2 cells, a human GCT-derived seminoma cell line which was used as an in vitro model for PGCs, showed proliferation defects upon TRIM71 knockdown. Additionally, in vitro growth competition assays, as well as proliferation assays with wild type and CRISPR/Cas9-generated TRIM71 mutant NCCIT cells showed that TRIM71 also promotes proliferation in this malignant GCT-derived non-seminoma cell line. Importantly, the PGC-specific markers BLIMP1 and NANOS3 were consistently downregulated in Trim71 KO PGCLCs, TRIM71 knockdown TCam-2 cells and TRIM71 mutant NCCIT cells. These data collectively support a role for TRIM71 in PGC development. Last, via exome sequencing analysis, we identified several TRIM71 variants in a cohort of infertile men, including a loss-of-function variant in a patient with an SCO phenotype. Altogether, our work reveals for the first time an association of TRIM71 deficiency with human male infertility, and uncovers further developmental roles for TRIM71 in the germline during mouse embryogenesis.

show abstract

Section: Resultsmentioning

confidence: 94%

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility

Fernández

Emich

Port

et al. 2021

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Consequently, TESE is offered to all NOA patients as the only treatment option. The etiology of MA is poorly understood, and although genetic factors are predicted to play a relevant role, among the 13 MA genes reported in more than one patient 3 – 6 only TEX11 mutations 7 and the complete AZFb deletion 8 are currently considered clinically relevant. Hence, the development of a pre-TESE diagnostic NOA gene panel would be of high clinical benefit to prevent unnecessary surgery in patients with pure MA.…”

Section: Introductionmentioning

confidence: 99%

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men

Krausz

Riera-Escamilla

Moreno-Mendoza

et al. 2020

Genetics in Medicine

Self Cite

View full text Add to dashboard Cite

Purpose: Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Methods: Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). Results: We found strong evidence for 5 novel genes likely responsible for MA ( ADAD2 , TERB1 , SHOC1 , MSH4 , and RAD21L1 ), for which mouse knockout (KO) models are concordant with the human phenotype. Four of them were validated in the two independent MA cohorts. In addition, 9 patients carried pathogenic variants in 7 previously reported genes - TEX14 , DMRT1 , TEX11 , SYCE1 , MEIOB , MEI1 and STAG3 - allowing to upgrade the clinical significance of these genes for diagnostic purposes. Our meiotic studies provide novel insight into the functional consequences of the variants, supporting their pathogenic role. Conclusions: Our findings contribute substantially to the development of a pre-TESE prognostic gene panel. If properly validated, the genetic diagnosis of complete MA prior to surgical interventions is clinically relevant. Wider implications include the understanding of potential genetic links between NOA and cancer predisposition, and between NOA and premature ovarian failure.

show abstract

“…Nineteen individuals had non-mosaic Klinefelter syndrome (47,XXY), nine had AZF microdeletions (seven AZFc microdeletions; two AZF b and c microdeletions), one had translocation (20;22)(q11.2;p11.1) [ 14 ], and one had inversion (1)(p22q44) [ 15 ].…”

Section: Methodsmentioning

confidence: 99%

Contribution of serum anti-Müllerian hormone in the management of azoospermia and the prediction of testicular sperm retrieval outcomes: a study of 155 adult men

Benderradji

Prasivoravong

Marcelli

et al. 2021

Basic Clin. Androl.

View full text Add to dashboard Cite

Background Testicular sperm extraction (TESE) is the method of choice for recovering spermatozoa in patients with azoospermia. However, the lack of reliable biomarkers makes it impossible to predict sperm retrieval outcomes at TESE. To date, little attention has been given to anti-Müllerian hormone (AMH) serum levels in adult men with altered spermatogenesis. In this study we aimed to investigate whether serum concentrations of AMH and the AMH to total testosterone ratio (AMH/T) might be predictive factors for sperm retrieval outcomes during TESE in a cohort of 155 adult Caucasian men with azoospermia. Results AMH serum levels were significantly lower in nonobstructive azoospermia (NOA) that was unexplained, cryptorchidism-related, cytotoxic and genetic (medians [pmol/l] = 30.1; 21.8; 26.7; 7.3; and p = 0.02; 0.001; 0.04; <0.0001, respectively]) compared with obstructive azoospermia (OA) (median = 44.8 pmol/l). Lowest values were observed in cases of genetic NOA (p < 0.0001, compared with unexplained NOA) and especially in individuals with non-mosaic Klinefelter syndrome (median = 2.3 pmol/l, p <0.0001). Medians of AMH/T values were significantly lower in genetic NOA compared to unexplained, cryptorchidism-related NOA as well as OA. Only serum concentrations of AMH differed significantly between positive and negative groups in men with non-mosaic Klinefelter syndrome. The optimal cut-off of serum AMH was set at 2.5 pmol/l. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of this cut-off to predict negative outcomes of SR were 100 %, 76.9 %, 66.6 %, 100 and 84.2 %, respectively. Conclusions Serum AMH levels, but not AMH/T values, are a good marker for Sertoli and germ cell population dysfunction in adult Caucasian men with non-mosaic Klinefelter syndrome and could help us to predict negative outcomes of SR at TESE with 100 % sensitivity when serum levels of AMH are below 2.5 pmol/l.

show abstract

SYCP2 Translocation-Mediated Dysregulation and Frameshift Variants Cause Human Male Infertility

Cited by 67 publications

References 103 publications

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility

TRIM71 Deficiency Causes Germ Cell Loss During Mouse Embryogenesis and Is Associated With Human Male Infertility

Genetic dissection of spermatogenic arrest through exome analysis: clinical implications for the management of azoospermic men

Contribution of serum anti-Müllerian hormone in the management of azoospermia and the prediction of testicular sperm retrieval outcomes: a study of 155 adult men

Contact Info

Product

Resources

About