Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility

Liu, Wenqiang; Li, Kunming; Bai, Dandan; Yin, Jie; Tang, Yuanyuan; Chi, Fengli; Zhang, Linfeng; Wang, Yu; Pan, Jiaping; Liang, Shanshan; Guo, Yi; Ruan, Jianbin; Kou, Xiaochen; Zhao, Yanhong; Wang, Hong; Chen, Jiayu; Teng, Xiaoming; Gao, Shaorong

doi:10.1007/s00439-017-1822-7

Cited by 69 publications

(51 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations within the ZP3 gene have been reported to be involved in human fertility. 16 Furthermore, we observed that the extent of gene-expression changes in relationship to changes in oestradiol levels also associated with the occurrence of mood symptoms, suggesting that the transcripts identified to predict PND may more generally serve as dynamic biomarker for hormone-induced mood changes, even in a pharmacological model. This raises the question of whether this candidate biomarker can identify women who display oestrogen sensitivity, even outside the pregnancystimulated state.…”

Section: Discussionmentioning

confidence: 85%

Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study

et al. 2018

View full text Add to dashboard Cite

BackgroundEnhanced sensitivity to oestrogen signalling may drive increased risk for depressive symptoms when exposed to peripartum sex-steroid hormone fluctuations.AimTesting if 116 pre-identified sex steroid-responsive transcripts that predicted perinatal depression (PND) translates to a pharmacological model of hormone-induced mood changes.MethodWe generated longitudinal, genome-wide gene-expression and DNA-methylation data from 60 women exposed to a gonadotrophin-releasing hormone agonist (GnRHa) or placebo. We used linear mixed-effect models to assess differences between baseline and follow-up for gene expression and DNA methylation in the biphasic ovarian response to GnRHa.ResultsOf the 116 PND-predictive transcripts, a significant (19%) overlap was observed with those differentially expressed post-GnRHa at both early and later follow-up, indicating sustained effects. Similarly, 49% of tested genes were differentially methylated post-GnRHa at the late follow-up. Within the GnRHa group, a large proportion of PND genes were significantly associated (gene expression; DNA methylation) with changes in depressive symptoms (28%; 66%), oestradiol levels (49%; 66%) and neocortex serotonin transporter binding (8%; 45%) between baseline and follow-up.ConclusionsOur data bridge clinical PND biomarkers with a pharmacological model of sex hormone-induced mood changes and directly relate oestrogen-induced biological changes with depressive symptoms and associated serotonin-signalling changes. Our data highlight that individual variations in molecular sensitivity to oestrogen associate with susceptibility to hormone-induced mood changes and hold promise for candidate biomarkers.Declaration of interestV.G.F. received honorarium for being a speaker for H. Lundbeck A/S. E.B.B. receives research funding from Böhringer Ingelheim to investigate FKBP5 as a potential drug target for depression.

show abstract

Section: Discussionmentioning

confidence: 85%

Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study

et al. 2018

View full text Add to dashboard Cite

show abstract

“…To assess the role of TGM6 in the pathogenesis of TB in vivo, we generated tgm6 -deficient mice by CRISPR/Cas9-mediated genome editing 24 , 25 (Supplementary Figure 6 ). We found that tgm6 homozygous knockout mice are not lethal (Supplementary Figure 7a ).…”

Section: Resultsmentioning

confidence: 99%

“…Tgm6 knockout mice was generated by the CRISPR/Cas9 method 24 , 25 . The tgm6 sgRNA were designed by targeting the exon4 of tgm6 and the sequences were listed in Supplementary Table 7 .…”

Section: Methodsmentioning

confidence: 99%

Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

Zheng

et al. 2018

Nat Commun

Self Cite

View full text Add to dashboard Cite

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb), and remains a leading public health problem. Previous studies have identified host genetic factors that contribute to Mtb infection outcomes. However, much of the heritability in TB remains unaccounted for and additional susceptibility loci most likely exist. We perform a multistage genome-wide association study on 2949 pulmonary TB patients and 5090 healthy controls (833 cases and 1220 controls were genome-wide genotyped) from Han Chinese population. We discover two risk loci: 14q24.3 (rs12437118, Pcombined = 1.72 × 10−11, OR = 1.277, ESRRB) and 20p13 (rs6114027, Pcombined = 2.37 × 10−11, OR = 1.339, TGM6). Moreover, we determine that the rs6114027 risk allele is related to decreased TGM6 transcripts in PBMCs from pulmonary TB patients and severer pulmonary TB disease. Furthermore, we find that tgm6-deficient mice are more susceptible to Mtb infection. Our results provide new insights into the genetic etiology of TB.

show abstract

“…A second female patient carrying one heterozygous nonsense mutation in ZP2 (c.2092C>T) and one heterozygous frameshift mutation in ZP3 (c.1045_1046insT) presented with infertility associated with the absence of zona formation. Mimicking these mutations in transgenic mice recapitulates the phenotype observed in the patient (Liu et al, 2017). A third case has reported 11 female patients from three different families carrying a heterozygous missense mutation in human ZP3 (c.400G>A), which is associated with empty follicle syndrome, due to the absence of the zona formation (Chen et al, 2017).…”

Section: Experimental Evidence For Species-specific Zona Recognitionmentioning

confidence: 81%

The molecular mechanisms mediating mammalian fertilization

2019

View full text Add to dashboard Cite

Fertilization is a key biological process in which the egg and sperm must recognize one another and fuse to form a zygote. Although the process is a continuum, mammalian fertilization has been studied as a sequence of steps: sperm bind and penetrate through the zona pellucida of the egg, adhere to the egg plasma membrane and finally fuse with the egg. Following fusion, effective blocks to polyspermy ensure monospermic fertilization. Here, we review how recent advances obtained using genetically modified mouse lines bring new insights into the molecular mechanisms regulating mammalian fertilization. We discuss models for these processes and we include studies showing that these mechanisms may be conserved across different mammalian species.

show abstract

Dosage effects of ZP2 and ZP3 heterozygous mutations cause human infertility

Cited by 69 publications

References 30 publications

Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study

Evidence for oestrogen sensitivity in perinatal depression: pharmacological sex hormone manipulation study

Genome-wide association study identifies two risk loci for tuberculosis in Han Chinese

The molecular mechanisms mediating mammalian fertilization

Contact Info

Product

Resources

About