Sperm morphological abnormalities in autosomal dominant polycystic kidney disease are associated with the Hippo signaling pathway via PC1.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder mostly caused by mutations in PKD1 or PKD2 genes. Here, we report thirteen ADPKD males with infertility and investigated the sperm morphological defects associated with PC1 disruption. Methods: Targeted next-generation sequencing was performed to detect PKD1 variants in patients. Sperm morphology was observed by immunostaining and transmission electron microscopy, and the sperm motility was assessed using the computer-assisted sperm analysis system. The Hippo signaling pathway was analyzed with by quantitative reverse transcription polymerase chain reaction (qPCR) and western blotting in vitro. Results: The ADPKD patients were infertile and their sperm tails showed morphological abnormalities, including coiled flagella, absent central microtubules, and irregular peripheral doublets. In addition, the length of sperm flagella was shorter in patients than in controls of in in. In vitro, ciliogenesis was impaired in Pkd1-depleted mouse kidney tubule cells. The absence of PC1 resulted in a reduction of MST1 and LATS1, leading to nuclear accumulation of YAP/TAZ and consequently increased transcription of Aurka. which might promote HDAC6-mediated ciliary disassembly. Conclusion: Our results suggest the dysregulated Hippo signaling significantly contributes to ciliary abnormalities in and may be associated with flagellar defects in spermatozoa from ADPKD patients.

Association of IL-4 and IL-10 Polymorphisms With Preterm Birth Susceptibility: A Systematic Review and Meta-Analysis.

Objective: Preterm birth (PTB) is a typical inflammatory disease with unclear pathogenesis. The studies investigating the relationship between anti-inflammatory factors IL-4 and IL-10 gene polymorphisms and PTB produced conflicting results. This systematic review and meta-analysis aimed to summarize the effects of IL-4 and IL-10 gene polymorphisms and clarify their possible association with PTB. Methods: A systematic literature review was conducted using PubMed, Web of Science, and Cochrane library (up to 02 April 2022). The MeSH terms, related entry terms, and other names in "Gene" database were used to find relevant articles. A fixed- or random-effects model was used to calculate the significance of IL-4 and IL-10 gene polymorphisms, depending on study heterogeneity. The odds ratios (OR) and 95% confidence intervals (CIs) were calculated in the allele, recessive, dominant, co-dominant, and over-dominant models. The Eggers publication bias plot was used to graphically represent the publication bias. Results: Polymorphisms in two interleukins (IL-4-590C/T (rs2243250) = 5 and IL-10-592A/C (rs1800872), -819T/C (rs1800871) and -1082A/G (rs1800896) = 16) were found in 21 articles. Overall, only the over-dominant gene model AA + GG vs. AG revealed significant association between IL-10-1082A/G (rs1800896) and PTB (OR [95% CI] = 0.87 [0.76, 0.99], p = 0.04). However, in the allele model, recessive model, dominant model, co-dominant model, and over-dominant model, the polymorphisms for IL-4-590C/T (rs2243250), IL-10-592A/C (rs1800872), and IL-10-819T/C (rs1800871) were not found to be associated with the risk of PTB. In gene models, no statistically significant association was found between IL-4-590C/T (rs2243250), IL-10-592A/C (rs1800872), IL-10-819T/C (rs1800871), and IL-10-1082A/G (rs1800896) polymorphisms and PTB in subgroup analyses by racial or control group Hardy-Weinberg Equilibrium (HWE) p-value. Eggers's publication bias plot and heterogeneity test (I2<50%, p = 0.05) of IL-10-1082A/G (rs1800896) suggested that the funnel asymmetry could be due to publication bias rather than heterogeneity. Conclusion: The current study suggests that the over-dominant gene model AA + GG vs. AG of IL-10-1082A/G (rs1800896) polymorphism may be associated with genetic susceptibility to PTB and may have a protective function against PTB risk. There was unclear association found between IL-4-590C/T (rs2243250), IL-10-592A/C (rs1800872) and IL-10-819T/C (rs1800871) polymorphisms and PTB. Due to the limitations of included studies and the risk of publication bias, additional research is required to confirm our findings. Systematic Review Registration: https://inplasy.com/inplasy-2022-4-0044, identifier INPLASY202240044.

Association of urinary bisphenol A concentrations with in vitro fertilisation outcomes: a systematic review and meta-analysis protocol.

INTRODUCTION: Bisphenol A (BPA) is a common environmental endocrine disruptor. BPA has been reported to be associated with female infertility, which may not only affect natural pregnancy and natural fertility but also affect the outcomes of in vitro fertilisation (IVF). BPA exposure may help to partly explain the unsatisfactory IVF outcomes, but the relationship between the concentrations of BPA in urine and IVF outcomes remains controversial. Therefore, we will perform a meta-analysis to identify and review the relationship between urinary BPA concentrations and IVF outcomes. METHODS AND ANALYSIS: A comprehensive literature search will be performed in PubMed, Web of Science and the Cochrane central register of controlled trials for relevant articles using MeSH terms and related entry terms (up to 20 April 2022). The language will be restricted to English. Articles will be screened for inclusion in or exclusion from the study independently by two reviewers after removing the duplicates. The titles and abstracts followed by full-text screening will also be conducted independently by two reviewers. In addition, the references of the included literature will also be traced to supplement our search results and to obtain all relevant literature. The Newcastle-Ottawa Scale will be used to assess the methodological quality of the included studies using a star rating system ranging from 0 to 9 stars. Heterogeneity in estimates from different articles will be quantified, and publication bias will be investigated using funnel plots. Finally, a sensitivity analysis will also be conducted to estimate whether our results could have been markedly affected by a single included study. ETHICS AND DISSEMINATION: Ethical approval is not required for this protocol, as participants are not included. Findings will be disseminated through peer-reviewed publications and conference presentations.

Associations of Sperm mtDNA Copy Number, DNA Fragmentation Index, and Reactive Oxygen Species With Clinical Outcomes in ART Treatments.

Recent studies have suggested that sperm mitochondrial DNA copy number (mtDNA-CN), DNA fragmentation index (DFI), and reactive oxygen species (ROS) content are crucial to sperm function. However, the associations between these measurements and embryo development and pregnancy outcomes in assisted reproductive technology (ART) remain unclear. Semen samples were collected from 401 participants, and seminal quality, parameters of sperm concentration, motility, and morphology were analyzed by a computer-assisted sperm analysis system. DFI, mtDNA-CN, and ROS levels were measured using sperm chromatin structure assay, real-time quantitative polymerase chain reaction, and ROS assay, respectively. Among the participants, 126 couples underwent ART treatments, including in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), and 79 of the couples had embryos transferred. In 401 semen samples, elevated mtDNA-CN and DFI were associated with poor seminal quality. In 126 ART couples, only mtDNA-CN was negatively correlated with the fertilization rate, but this correlation was not significant after adjusting for male age, female age, seminal quality, ART strategy, number of retrieved oocytes, controlled stimulation protocols, and cycle rank. Regarding pregnancy outcomes, sperm mtDNA-CN, ROS, and DFI were not associated with the clinical pregnancy rate or live birth rate in 79 transferred cases. In conclusion, increased mtDNA-CN and DFI in sperm jointly contributed to poor seminal quality, but sperm mtDNA-CN, ROS, and DFI were not associated with clinical outcomes in ART.

Case Report: Preimplantation Genetic Testing and Pregnancy Outcomes in Women With Alport Syndrome.

BACKGROUND: Alport syndrome, a monogenic kidney disease, is characterized by progressive hemorrhagic nephritis, sensorineural hearing loss, and ocular abnormalities. Mutations in COL4A5 at Xq22 accounts for 80-85% of X-linked Alport syndrome patients. Three couples were referred to our reproductive genetics clinic for prenatal or preconception counseling. METHODS: Prenatal diagnoses were performed by amplifying targeted regions of COL4A5. Targeted next-generation sequencing (NGS)-based haplotype analysis or karyomapping was performed in two patients. Pregnancy outcomes in the three patients were collected and analyzed. Published Alport syndrome cases were searched in Pubmed and Embase. RESULTS: Prenatal diagnoses in two cases showed one fetus harbored the same pathogenic mutation as the proband and the other was healthy. The couple with an affected fetus and the patient with a family history of Alport syndrome chose to take the preimplantation genetic testing (PGT) procedure. One unaffected embryo was transferred to the uterus, and a singleton pregnancy was achieved, respectively. Two patients presented non-nephrotic range proteinuria (<3 g/24 h) during pregnancy and the three cases all delivered at full-term. However, published Alport cases with chronic kidney disease or proteinuria during pregnancy were came with a high rate (75%) of adverse maternal and fetal outcomes. CONCLUSION: The PGT procedure performed in this study was proven to be practicable and might be expanded to be applied in other monogenic diseases. Moderate or severe renal impairments in Alport syndrome were strongly associated with adverse maternal and fetal outcomes, and baseline proteinuria was a potential predictor for pregnancy outcomes of Alport syndrome as other kidney diseases.

Kabuki syndrome: review of the clinical features, diagnosis and epigenetic mechanisms.

BACKGROUND: Kabuki syndrome (KS), is a infrequent inherited malformation syndrome caused by mutations in a H3 lysine 4 methylase (KMT2D) or an X-linked histone H3 lysine 27 demethylase (UTX/KDM6A). The characteristics in patients with KS have not yet been well recognized. DATA SOURCES: We used databases including PubMed and Google Scholar to search for publications about the clinical features and the etiology of Kabuki syndrome. The most relevant articles to the scope of this review were chosen for analysis. RESULTS: Clinical diagnosis of KS is challenging in initial period, because many clinical characteristics become apparent only in subsequent years. Recently, the genetic and functional interaction between KS-associated genes and their products have been elucidated. New clinical findings were reported including nervous system and intellectual performance, endocrine-related disorders and immune deficiency and autoimmune disease. Cancer risks of Kabuki syndrome was reviewed. Meanwhile, we discussed the Kabuki-like syndrome. Digital clinical genetic service, such as dysmorphology database can improve availability and provide high-quality diagnostic services. Given the significant clinical relevance of KS-associated genes and epigenetic modifications crosstalk, efforts in the research for new mechanisms are thus of maximum interest. CONCLUSIONS: Kabuki syndrome has a strong clinical and biological heterogeneity. The main pathogenesis of Kabuki syndrome is the imbalance between switch-on and -off of the chromatin. The direction of drug research may be to regulate the normal opening of chromatin. Small molecule inhibitors of histone deacetylases maybe helpful in treatment of mental retardation and reduce cancer risk in KS.