Identification novel mutations and phenotypic spectrum expanding in PATL2 in infertile women with IVF/ICSI failure.

AIM: Abnormalities in oocyte maturation, fertilization, and early embryonic development are major causes of primary infertility in women who are undergoing IVF/ICSI attempts. Although many genetic factors responsible for these abnormal phenotypes have been identified, there are more additional pathogenic genes and variants yet to be discovered. Previous studies confirmed that bi-allelic PATL2 deficiency is an important factor for female infertility. In this study, 935 infertile patients with IVF/ICSI failure were selected for whole-exome sequencing, and 18 probands carrying PATL2 variants with a recessive inheritance pattern were identified. METHODS: We estimated that the prevalence contributed by PATL2 was 1.93% (18/935) in our study cohort. RESULTS: 15 novel variants were found in those families, including c.1093C > T, c.1609dupA, c.1204C > T, c.643dupG, c.877-2A > G, c.1228C > G, c.925G > A, c.958G > A, c.4A > G, c.1258T > C, c.1337G > A, c.1264dupA, c.88G > T, c.1065-2A > G, and c.1271T > C. The amino acids altered by the corresponding variants were highly conserved in mammals, and in silico analysis and 3D molecular modeling suggested that the PATL2 mutants impaired the physiologic function of the resulting proteins. Diverse clinical phenotypes, including oocyte maturation defect, fertilization failure, and early embryonic arrest might result from different variants of PATL2. CONCLUSIONS: These results expand the spectrum of PATL2 variants and provide an important reference for genetic counseling for female infertility, and they increase our understanding of the mechanisms of oocyte maturation arrest caused by PATL2 deficiency.

The effects of caloric restriction and a high-fat diet on ovarian lifespan and the expression of SIRT1 and SIRT6 proteins in rats.

BACKGROUND AND AIMS: Caloric restriction (CR) extends mammals' lifespans and suppresses ovary development. Sirtuins are involved in these mechanisms. If, and to what extent CR affects ovarian lifespan and follicle development is largely unknown. We investigated the effects of moderate and severe caloric restriction compared with a high-fat dietary regimen on ovarian follicle reserves in rats. METHODS: Female Sprague-Dawley rats (n=48) randomly divided into four groups including normal control (NC), 25% caloric restriction (MCR), 45% CR (SCR) and high-fat diet (HF) were maintained on these regimens for 2 months. RESULTS: Histological analysis showed that both the 25 and 45% CR rats had a significantly higher percentage of primordial follicles and a larger number of healthy follicles than the NC rats, whereas the HF rats did not differ significantly from the NC rats. Immunohistochemical analysis revealed that SIRT1 and SIRT6 proteins were present in the nucleus and cytoplasm of the oocytes. The 25% CR diet increased the expression of both SIRT1 and SIRT6 in the ovary, whereas the 45% CR and HF diets caused a decrease in SIRT1 expression. The level of SIRT6 protein did not change with the 45% CR diet, and it appeared slightly lower in the HF than in the NC groups. CONCLUSIONS: Caloric restriction may inhibit the transition from primordial to developing follicles and extend the entire growth phase of a follicle to preserve the reserve of germ cells. SIRT1 and SIRT6 are both associated with these effects.

Calorie restriction increases primordial follicle reserve in mature female chemotherapy-treated rats.

UNLABELLED: We assessed the effects of calorie restriction (CR)-mediated protection against chemotherapy damage on ovarian reserve. Forty-eight female Sprague-Dawley rats were randomly divided into four groups: the normal control group (NC group, fed ad libitum), the CR group (fed with 65% food intake of the NC group), the CTX group (injected with cyclophosphamide (CTX) and fed ad libitum), and the CR+CTX group (injected with CTX and fed with 65% food intake of the NC group). Ovarian reserve was examined by vaginal smears and follicle counting. SIRT1 is a deacetylase that is activated by a variety of stressors and targets transcriptional regulators including p53, NF-κB, FOXO1, 3, and 4, and the transcriptional regulator PGC-1α. The expression level of SIRT1, p53 and FOXO3a in the ovary was measured by western blot. CR did not interfere with estrous cycling but maintained estrous cycling in CTX-treated CR rats. The number of primordial follicles in the CR rats was comparable to the NC group, and CR+CTX group rats had more primordial follicles and primary follicles than the CTX group. SIRT1 expression in the ovary was higher in the CR group compared to the control group, and p53 level was lower in the CR group than that in the NC group. There is no significant difference in the expression level of FOXO3a between the CR group and the NC group. CONCLUSIONS: These results indicate that CR can increase the ovarian follicular reserve and reduce the CTX-induced ovarian damage, and CR positive effects may be due to its intervention in the transition from primordial to primary follicle, and its reduction of oxidative stress.

[Reduced cardiopulmonary exercise capacity in patients with essential hypertension: impact of left ventricular hypertrophy].

OBJECTIVE: To evaluate the cardiopulmonary exercise capacity in patients with essential hypertension (EH) complicating with or without left ventricular hypertrophy (LVH). METHODS: Graded maximal exercise test on the bicycle ergometer with respiratory gas analysis were performed in 30 gender and age matched normotensive controls, 40 EH patients without LVH and 30 EH patients with LVH (LVMI>125 g/m2 in males and > 120 g/m2 in females). Metabolic equivalents (METs), oxygen uptake (VO2), oxygen uptake to body mass ratio (VO2/kg) and oxygen uptake to heart beat ratio (VO2/HR) at time of reaching anaerobic threshold (AT) and at maximal oxygen uptake (VO2max) were measured and compared. RESULTS: METs and VO2/kg were significantly reduced in EH patients with or without LVH compared with controls [at AT, METs: 3.57 +/- 0.8 and 4.34 +/- 1.47 vs. 5.21 +/- 1.45; VO2/kg: 12.38 +/- 2.85 and 14.42 +/- 4.33 vs. 18.48 +/- 4.52, all P < 0.01; at VO2max, METs: 4.94 +/- 1.24 and 5.90 +/- 1.51 vs. 6.96 +/- 1.85; VO(2)/kg: (17.20 +/- 4.34) mlxmin(-1)xkg(-1) and (20.41 +/- 4.59) mlxmin(-1)xkg(-1) vs. (24.04 +/- 5.21) mlxmin(-1)xkg(-1), all P < 0.01]. METs and VO2/kg at both time points were also significantly reduced in EH patients with LVH compared EH patients without LVH (all P < 0.05). The lower VO2/kg in hypertensive patients was significantly correlated to higher LVMI (P < 0.05). CONCLUSIONS: Cardiopulmonary exercise capacity was reduced in hypertensive patients, especially in hypertensive patients with LVH.