Cryptic splice site poisoning and meiotic arrest caused by a homozygous frameshift mutation in RBMXL2: A case report.

Gene expression in meiotic cells in the testis is characterized by intense transcriptional activity and alternative splicing. These processes are mainly controlled by RNA-binding proteins expressed strongly in germ cells. Functional impairments in any of these proteins' functions can lead to defects in meiosis and thus severe male infertility. Here, we have identified a homozygous frameshift mutation (NM_014469.4:c.301dup; p.Ser101LysfsTer29) in the RNA-binding motif protein, X-linked like 2 (RBMXL2) gene in a man with an azoospermia due to meiotic arrest. As RBMXL2 is known to be crucial for safeguarding the meiotic transcriptome in mice testes, we hypothesized that this variant leads to cryptic splice site poisoning. To determine the variant's impact on spermatogenesis, we confirmed the absence of RBMXL2 protein in the patient's testis tissue and then evidenced abnormal expression of several spermatogenesis proteins (e.g. meiosis-specific with coiled-coil domain) known to be altered in rbmxl2 knock-out mice with meiotic arrest. Our results indicate that RBMXL2's function in spermatogenesis is conserved in mammals. We hypothesize that deleterious variant in the RBMXL2 gene can result in male infertility and complete meiotic arrest, due to the disruption of gene expression by cryptic splice site poisoning.

Real-world effectiveness of Fertistartkit® treatment in women undergoing ART in French clinical practice: a retrospective multicentre study.

RESEARCH QUESTION: What is the real-world effectiveness of Fertistartkit® in women undergoing assisted reproductive technology (ART)? DESIGN: Retrospective cohort study including anonymized data of women undergoing ovarian stimulation for ART with Fertistartkit between April 2016 and November 2017 and follow-up of clinical outcomes up to February 2018. Data were collected from the electronic patient databases of 12 French ART centres. The main outcome was number of oocytes retrieved. All data were categorized according to female age (<25, 25-29, 30-34, 35-37, 38-39 and >39 years). RESULTS: A total of 1006 cycles from 914 women treated with Fertistartkit were included. At the time of first ovarian stimulation in the study, women were 34.9 ± 5.0 years old, with a median body mass index of 22.7 kg/m². Couples had been infertile for more than 4 years, with all patterns of causes of infertility. Ovarian stimulation was started with a median dose of 300 IU (interquartile range [IQR]: 150-300 IU) of Fertistartkit for 10 days (IQR: 9-11 days), so a median total dose of 2700 IU (IQR: 1800-3300 IU). The mean number of oocytes retrieved per cycle was 9.5 ± 6.8, and the mean number of mature oocytes per cycle was 7.4 ± 5.5. The obtained ongoing pregnancy per started cycle was 26.0% (95% confidence interval [CI]: 24.1-27.9) and the obtained ongoing pregnancy per puncture was 27.0% (95% CI: 25.0-29.0). CONCLUSIONS: This is the first cohort to describe Fertistartkit treatment management in real-life conditions. The real-world data show that Fertistartkit is an effective option for ovarian stimulation.

Comparison of human embryomorphokinetic parameters in sequential or global culture media.

A prospective study on randomized patients was conducted to determine how morphokinetic parameters are altered in embryos grown in sequential versus global culture media. Eleven morphokinetic parameters of 160 single embryos transferred were analyzed by time lapse imaging involving two University-affiliated in vitro fertilization (IVF) centers. We found that the fading of the two pronuclei occurred earlier in global (22.56±2.15 hpi) versus sequential media (23.63±2.71 hpi; p=0.0297). Likewise, the first cleavage started earlier at 24.52±2.33 hpi vs 25.76±2.95 hpi (p=0.0158). Also, the first cytokinesis was shorter in global medium, lasting 18±10.2 minutes in global versus 36±37.8 minutes in sequential culture medium (p <0.0001). We also observed a significant shortening in the duration of the 2-cell stage in sequential medium: 10.64 h±2.75 versus 11.66 h±1.11 in global medium (p=0.0225) which suggested a faster progression of the embryos through their first mitotic cell cycle. In conclusion, morphokinetic analysis of human embryos by Time lapse imaging reveals significant differences in five kinetic variables according to culture medium. Our study highlights the need to adapt morphokinetic analysis accordingly to the type of media used to best support human early embryo development.

[Assisted oocyte activation: a new tool for severe male factor infertility treatment]. / Aide à l'activation ovocytaire - Un nouvel atout dans le traitement des infertilités masculines sévères.

In severe male infertility, in vitro fertilization (IVF) with intra-cytoplasmic sperm injection (ICSI) represents the sole available therapeutic option. However this technique is not always successful in promoting fertilization, as some couples completely and repeatedly fail to obtain any embryo. In many cases, this failure can be attributed to a defective rise in intracellular calcium, which is required to achieve oocyte activation. Over the last twenty years, several laboratories dedicated to assisted reproduction technologies have been using a calcium ionophore to assist oocyte activation. The aim of this review is to give an overview of the advances and consequences associated with this new technique referred to as assisted oocyte activation.